Pre-organized tricyclic integrase inhibitor compounds

ABSTRACT

Tricyclic compounds according to the structure below, protected intermediates thereof, and methods for inhibition of HIV-integrase are disclosed. 
     
       
         
         
             
             
         
       
     
     A 1  and A 2  are moieties forming a five, six, or seven membered ring. L is a bond or a linker connecting a ring atom of Ar to N. X is O, S, or substituted nitrogen. Ar is aryl or heteroaryl, Q is N,  + NR, or CR 4 . The aryl carbons may be independently substituted with substituents other than hydrogen. The compounds may include prodrug moieties covalently attached at any site.

This non-provisional application is a divisional of non-provisionalapplication Ser. No. 10/687,373, filed Oct. 16, 2003, that claims thebenefit of Provisional Application No. 60/418,963, filed Oct. 16, 2002,and Provisional Application No. 60/478,783, filed Jun. 16, 2003, all ofwhich are incorporated herein in their entirety by reference as if eachwere individually incorporated herein by reference.

FIELD OF THE INVENTION

The invention relates generally to compounds with antiviral activity andmore specifically with HIV-integrase inhibitory properties.

BACKGROUND OF THE INVENTION

Human immunodeficiency virus (HIV) infection and related diseases are amajor public health problem worldwide. A virally encoded integraseprotein mediates specific incorporation and integration of viral DNAinto the host genome. Integration is necessary for viral replication.Accordingly, inhibition of HIV integrase is an important therapeuticpursuit for treatment of HIV infection of the related diseases.

Human immunodeficiency virus type 1 (HIV-1) encodes three enzymes whichare required for viral replication: reverse transcriptase, protease, andintegrase. Although drugs targeting reverse transcriptase and proteaseare in wide use and have shown effectiveness, particularly when employedin combination, toxicity and development of resistant strains havelimited their usefulness (Palella, et al N. Engl. J. Med. (1998)338:853-860; Richman, D. D. Nature (2001) 410:995-1001). There is a needfor new agents directed against alternate sites in the viral life cycle.Integrase has emerged as an attractive target, because it is necessaryfor stable infection and homologous enzymes are lacking in the humanhost (LaFemina, et al J. Virol. (1992) 66:7414-7419). The function ofintegrase is to catalyze integration of proviral DNA, resulting from thereverse transcription of viral RNA, into the host genome, by a stepwisefashion of endonucleolytic processing of proviral DNA within acytoplasmic preintegration complex (termed 3′-processing or “3′-P”) withspecific DNA sequences at the end of the HIV-1 long terminal repeat(LTR) regions, followed by translocation of the complex into the nuclearcompartment where integration of 3′-processed proviral DNA into host DNAoccurs in a “strand transfer” (ST) reaction (Hazuda, et al Science(2000) 287:646-650; Katzman, et al Adv. Virus Res. (1999) 52:371-395;Asante-Applah, et al Adv. Virus Res. (1999) 52:351-369). Althoughnumerous agents potently inhibit 3′-P and ST in extracellular assaysthat employ recombinant integrase and viral long-terminal-repeatoligonucleotide sequences, often such inhibitors lack inhibitory potencywhen assayed using fully assembled preintegration complexes or fail toshow antiviral effects against HIV-infected cells (Pommier, et al Adv.Virus Res. (1999) 52-427-458; Farnet, et al Proc. Natl. Acad. Sci.U.S.A. (1996) 93:9742-9747; Pommier, et al Antiviral Res. (2000)47:139-148.

Certain HIV integrase inhibitors have been disclosed which blockintegration in extracellular assays and exhibit good antiviral effectsagainst HIV-infected cells (Anthony, et al WO 02/30426; Anthony, et alWO 02/30930; Anthony, et al WO 02/30931; WO 02/055079; Zhuang, et al WO02/36734; U.S. Pat. No. 6,395,743; U.S. Pat. No. 6,245,806; U.S. Pat.No. 6,271,402; Fujishita, et al WO 00/039086; Uenaka et al WO 00/075122;Selnick, et al WO 99/62513; Young, et al WO 99/62520; Payne, et al WO01/00578; Jing, et al Biochemistry (2002) 41:5397-5403; Pais, et alJour. Med. Chem. (2002) 45:3184-94; Goldgur, et al Proc. Natl. Acad.Sci. U.S.A. (1999) 96:13040-13043; Espeseth, et al Proc. Natl. Acad.Sci. U.S.A. (2000) 97:11244-11249).

HIV integrase inhibitory compounds with improved antiviral andpharmacokinetic properties are desirable, including enhanced activityagainst development of HIV resistance, improved oral bioavailability,greater potency and extended effective half-life in vivo (Nair, V. “HIVintegrase as a target for antiviral chemotherapy” Reviews in MedicalVirology (2002) 12(3):179-193). Three-dimensional quantitativestructure-activity relationship studies and docking simulations(Buolamwini, et al Jour. Med. Chem. (2002) 45:841-852) ofconformationally-restrained cinnamoyl-type integrase inhibitors (Artico,et al Jour. Med. Chem. (1998) 41:3948-3960) have correlatedhydrogen-bonding interactions to the inhibitory activity differencesamong the compounds.

Improving the delivery of drugs and other agents to target cells andtissues has been the focus of considerable research for many years.Though many attempts have been made to develop effective methods forimporting biologically active molecules into cells, both in vivo and invitro, none has proved to be entirely satisfactory. Optimizing theassociation of the inhibitory drug with its intracellular target, whileminimizing intercellular redistribution of the drug, e.g. to neighboringcells, is often difficult or inefficient.

Most agents currently administered parenterally to a patient are nottargeted, resulting in systemic delivery of the agent to cells andtissues of the body where it is unnecessary, and often undesirable. Thismay result in adverse drug side effects, and often limits the dose of adrug (e.g., cytotoxic agents and other anti-cancer or anti-viral drugs)that can be administered. By comparison, although oral administration ofdrugs is generally recognized as a convenient and economical method ofadministration, oral administration can result in either (a) uptake ofthe drug through the cellular and tissue barriers, e.g. blood/brain,epithelial, cell membrane, resulting in undesirable systemicdistribution, or (b) temporary residence of the drug within thegastrointestinal tract. Accordingly, a major goal has been to developmethods for specifically targeting agents to cells and tissues. Benefitsof such treatment includes avoiding the general physiological effects ofinappropriate delivery of such agents to other cells and tissues, suchas uninfected cells. Intracellular targeting may be achieved by methodsand compositions which allow accumulation or retention of biologicallyactive agents inside cells.

SUMMARY OF THE INVENTION

The present invention provides compositions and methods for inhibitionof HIV integrase.

In one aspect, the invention comprises a compound having the structure:

wherein:

A¹ and A² are independently selected from O, S, NR, C(R²)₂, CR²OR,CR²OC(═O)R, C(═O), C(═S), CR²SR, C(═NR), C(R²)₂—C(R³)₂, C(R²)═C(R³),C(R²)₂—O, NR—C(R³)₂, N═C(R³), N═N, SO₂—NR, C(═O)C(R³)₂, C(═O)NR,C(R²)₂—C(R³)₂—C(R³)₂, C(R²)═(R³)—C(R³)₂, C(R²)C(═O)NR, C(R²)C(═S)NR,C(R²)═N—C(R³)₂, C(R²)═N—NR, and N═C(R³)—NR;

Q is N, ⁺NR, or CR⁴;

L is selected from a bond, O, S, S—S, S(═O), S(═O)₂, S(═O)₂NR, NR, N—OR,C₁-C₁₂ alkylene, C₁-C₁₂ substituted alkylene, C₂-C₁₂ alkenylene, C₂-C₁₂substituted alkenylene, C₂-C₁₂ alkynylene, C₂-C₁₂ substitutedalkynylene, C(═O)NH, OC(═O)NH, NHC(═O)NH, C(═O), C(═O)NH(CH₂)_(n), or(CH₂CH₂O)_(n), where n may be 1, 2, 3, 4, 5, or 6;

X is selected from O, S, NH, NR, N—OR, N—NR₂, N—CR₂OR and N—CR₂NR₂;

Ar is selected from C₃-C₁₂ carbocycle, C₃-C₁₂ substituted carbocycle,C₆-C₂₀ aryl, C₆-C₂₀ substituted aryl, C₂-C₂₀ heteroaryl, and C₂-C₂₀substituted heteroaryl;

R¹ R², R³ and R⁴ are each independently selected from H, F, Cl, Br, I,OH, —NH₂, —NH₃ ⁺, —NHR, —NR₂ ⁺, —NR₃ ⁺, C₁-C₈ alkylhalide, carboxylate,sulfate, sulfamate, sulfonate, 5-7 membered ring sultam, C₁-C₈alkylsulfonate, C₁-C₈ alkylamino, 4-dialkylaminopyridinium, C₁-C₈alkylhydroxyl, C₁-C₈ alkylthiol, dialkylaminopyridinium, —SO₂R, —SO₂Ar,—SOAr, —SAr, —SO₂NR₂, —SOR, —CO₂R, —C(═O)NR₂5-7 membered ring lactam,5-7 membered ring lactone, —CN, —N₃, —NO₂, C₁-C₈ alkoxy, C₁-C₈trifluoroalkyl, C₁-C₈ alkyl, C₁-C₈ substituted alkyl, C₃-C₁₂ carbocycle,C₃-C₁₂ substituted carbocycle, C₆-C₂₀ aryl, C₆-C₂₀ substituted aryl,C₂-C₂₀ heteroaryl, and C₂-C₂₀ substituted heteroaryl, polyethyleneoxy,phosphonate, phosphate, and a prodrug moiety;

when taken together on a single carbon, two R² or two R³ may form aspiro ring; and

R is independently selected from H, C₁-C₈ alkyl, C₁-C₈ substitutedalkyl, C₆-C₂₀ aryl, C₆-C₂₀ substituted aryl, C₂-C₂₀ heteroaryl, andC₂-C₂₀ substituted heteroaryl, polyethyleneoxy, phosphonate, phosphate,and a prodrug moiety;

R^(X2) is independently selected from H, C₁-C₈ alkyl, C₁-C₈ substitutedalkyl, C₆-C₂₀ aryl, C₆-C₂₀ substituted aryl, C₂-C₂₀ heteroaryl, andC₂-C₂₀ substituted heteroaryl, polyethyleneoxy, phosphonate, phosphate,a prodrug, a pharmaceutically acceptable prodrug, a prodrug moiety, aprotecting group, and a phosphonate prodrug moiety;

and the salts, solvates, resolved enantiomers and purified diastereomersthereof;

with the proviso that when Y=Z is C═C(OH), X is O, A¹ is C(═O), A² isC(R²)═C(R³), and Q is CH, then L is not a bond.

In one aspect, the invention is a compound having the structure:

wherein:

A¹ is independently selected from C(R²)₂, CR²OR, CR²OC(═O)R, C(═O),C(═S), CR²SR, and C(═NR),

A² is independently selected from C(R²)₂—C(R³)₂, C(R²)═C(R³), andC(═O)C(R³)₂;

Q is CR⁴;

L is selected from a bond, O, S, S—S, S(═O), S(═O)₂, S(═O)₂NR, NR, N—OR,C₁-C₁₂ alkylene, C₁-C₁₂ substituted alkylene, C₂-C₁₂ alkenylene, C₂-C₂substituted alkenylene, C₂-C₁₂ alkynylene, C₂-C₁₂ substitutedalkynylene, C(═O)NH, OC(═O)NH, NHC(═O)NH, C(═O), C(═O)NH(CH₂)_(n), or(CH₂CH₂O)_(n), where n is optionally 1, 2, 3, 4, 5, or 6;

X is selected from O, S, NH, NR, N—OR, N—NR₂, N—CR₂OR and N—CR₂NR₂;

Ar is selected from (a) a C₃-C₁₂ carbocycle, C₃-C₁₂ substitutedcarbocycle, C₆-C₂₀ aryl, C₆-C₂₀ substituted aryl, C₂-C₂₀ heteroaryl, andC₂-C₂₀ substituted heteroaryl;

or (b) a saturated, unsaturated or aromatic ring or ring system having amono- or bicyclic carbocycle or heterocycle containing 3 to 12 ringatoms;

R², R³ and R⁴ are each independently selected from H, F, Cl, Br, I, OH,—NH₂, —NH₃ ⁺, —NHR, —NR₂, —NR₃ ⁺, C₁-C₈ alkylhalide, carboxylate,sulfate, sulfamate, sulfonate, 5-7 membered ring sultam, C₁-C₈alkylsulfonate, C₁-C₈ alkylamino, 4-dialkylaminopyridinium, C₁-C₈alkylhydroxyl, C₁-C₈ alkylthiol, —SO₂R, —SO₂Ar, —SOAr, —SAr, —SO₂R₂,—SOR, —CO₂R, —C(═O)NR₂, 5-7 membered ring lactam, 5-7 membered ringlactone, —CN, —N₃, —NO₂, C₁-C₈ alkoxy, C₁-C₈ trifluoroalkyl, C₁-C₈alkyl, C₁-C₈ substituted alkyl, C₃-C₁₂ carbocycle, C₃-C₁₂ substitutedcarbocycle, C₆-C₂₀ aryl, C₆-C₂₀ substituted aryl, C₂-C₂₀ heteroaryl, andC₂-C₂₀ substituted heteroaryl, polyethyleneoxy, phosphonate, phosphate,and a prodrug moiety;

when taken together on a single carbon, two R² or two R³ may from aspiro ring; R¹ is independently selected from CR₃, NRSO₂R, OC(═O)NR₂OC(═O)R, SR, H, F, Cl, Br, I, OH, —NH₂, —NH₃ ⁺, —NHR, —NR₂, —NR₃ ⁺,C₁-C₈ alkylhalide, carboxylate, sulfate, sulfamate, sulfonate, 5-7membered ring sultam, C₁-C₈ alkylsulfonate, C₁-C₈ alkylamino,4-dialkylaminopyridinium, C₁-C₈ alkylhydroxyl, C₁-C₈ alkylthiol, —SO₂R,—SO₂Ar, —SOAr, —SAr, —SO₂NR₂, —SOR, —CO₂R, —C(═O)NR₂, 5-7 membered ringlactam, 5-7 membered ring lactone, —CN, —N₃, —NO₂, C₁-C₈ alkoxy, C₁-C₈trifluoroalkyl, C₁-C₈ alkyl, C₁-C₈ substituted alkyl, C₃-C₁₂ carbocycle,C₃-C₁₂ substituted carbocycle, C₆-C₂₀ aryl, C₆-C₂₀ substituted aryl,C₂-C₂₀ heteroaryl, and C₂-C₂₀ substituted heteroaryl, polyethyleneoxy,phosphonate, phosphate, and a prodrug moiety;

R is independently selected from H, C₁-C₈ alkyl, C₁-C₈ substitutedalkyl, C₆-C₂₀ aryl, C₆-C₂₀ substituted aryl, C₂-C₂₀ heteroaryl, andC₂-C₂₀ substituted heteroaryl, polyethyleneoxy, phosphonate, phosphate,and a prodrug moiety;

R^(X2) is independently selected from H, C₁-C₈ alkyl, C₁-C₈ substitutedalkyl, C₆-C₂₀ aryl, C₆-C₂₀ substituted aryl, C₂-C₂₀ heteroaryl, andC₂-C₂₀ substituted heteroaryl, polyethyleneoxy, phosphonate, phosphate,a prodrug moiety, and a protecting group;

and the tautomers, salts, solvates, resolved enantiomers and purifieddiastereomers thereof,

with the proviso that when Y=Z is C═C(OH), X is O, A¹ is C(═O), A² isC(R²)═C(R³), and Q is CH, then L is not a bond.

In another aspect the invention is a compound having the structure:

wherein:

A¹ is independently selected from C(R²)₂—C(R³)₂, C(R²)═C(R³),C(═O)C(R³)₂, C(R²)₂—C(R³)₂—C(R³)₂, C(R²)═C(R³)—C(R³)₂, andC(R²)₂—C(R³)═C(R³);

A² is independently selected from C(R²)₂—C(R³)₂, C(R²)═C(R³), andC(═O)C(R³)₂;

Q is CR⁴;

L is selected from a bond, O, S, S—S, S(═O), S(═O)₂, S(═O)₂NR, NR, N—OR,C₁-C₁₂ alkylene, C₁-C₁₂ substituted alkylene, C₂-C₁₂ alkenylene, C₂-C₁₂substituted alkenylene, C₂-C₁₂ alkynylene, C₂-C₁₂ substitutedalkynylene, C(═O)N—H, OC(═O)NH, NHC(═O)NH, C(—O), C(═O)NH(CH₂)_(n), or(CH₂CH₂O)_(n), where n may be 1, 2, 3, 4, 5, or 6;

X is selected from O, S, NH, NR, N—OR, N—NR₉, N—CR₂OR and N—CR₉NR₂;

Ar is selected from (a) a C₃-C₁₂ carbocycle, C₃-C₁₂ substitutedcarbocycle, C₆-C₂₀ aryl, C₆-C₂₀ substituted aryl, C₂-C₂₀ heteroaryl, andC₂-C₂₀ substituted heteroaryl;

or (b) a saturated, unsaturated or aromatic ring or ring system having amono- or bicyclic carbocycle or heterocycle containing 3 to 12 ringatoms;

R², R³ and R⁴ are each independently selected from H, F, Cl, Br, I, OH,—NH₂, —NH₃ ⁺, —NHR, —NR₂, —NR₃ ⁺, C₁-C₈ alkylhalide, carboxylate,sulfate, sulfamate, sulfonate, 5-7 membered ring sultam, C₁-C₈alkylsulfonate, C₁-C₈ alkylamino, 4-dialkylaminopyridinium, C₁-C₈alkylhydroxyl, C₁-C₈ alkylthiol, —SO₂R, —SO₂Ar, —SOAr, —SAr, —SO₂NR₂,—SOR, —CO₂R, —C(═O)NR₂, 5-7 membered ring lactam, 5-7 membered ringlactone, —CN, —N₃, —NO₂, C₁-C₈ alkoxy, C₁-C₈ trifluoroalkyl, C₁-C₈alkyl, C₁-C₈ substituted alkyl, C₃-C₁₂ carbocycle, C₃-C₁₂ substitutedcarbocycle, C₆-C₂₀ aryl, C₆-C₂₀ substituted aryl, C₂-C₂₀ heteroaryl, andC₂-C₂₀ substituted heteroaryl, polyethyleneoxy, phosphonate, phosphate,and a prodrug moiety;

when taken together on a single carbon, two R² or two R³ may form aspiro ring;

R¹ is independently selected from CR₃, NRSO₂R, OC(═O)NR₂ OC(═O)R, SR, H,F, Cl, Br, I, OH, —NH₂, —NH₃ ⁺, —NHR, —NR₂, —NR₃ ⁺, C₁-C₈ alkylhalide,carboxylate, sulfate, sulfamate, sulfonate, 5-7 membered ring sultam,C₁-C₈ alkylsulfonate, C₁-C₈ alkylamino, 4-dialkylaminopyridinium, C₁-C₈alkylhydroxyl, C₁-C₈ alkylthiol, —SO₂R, —SO₂Ar, —SOAr, —SAr, —SO₂NR₂,—SOR, —CO₂R, —C(═O)NR₂, 5-7 membered ring lactam, 5-7 membered ringlactone, —CN, —N₃, —NO₂, C₁-C₈ alkoxy, C₁-C₈ trifluoroalkyl, C₁-C₈alkyl, C₁-C₈ substituted alkyl, C₃-C₁₂ carbocycle, C₃-C₁₂ substitutedcarbocycle, C₆-C₂₀ aryl, C₆-C₂₀ substituted aryl, C₂-C₂₀ heteroaryl, andC₂-C₂₀ substituted heteroaryl, polyethyleneoxy,phosphonate, phosphate,and a prodrug moiety;

R is independently selected from H, C₁-C₈ alkyl, C₁-C₈ substitutedalkyl, C₆-C₂₀ aryl, C₆-C₂₀ substituted aryl, C₂-C₂₀ heteroaryl, andC₂-C₂₀ substituted heteroaryl, polyethyleneoxy, phosphonate, phosphate,and a prodrug moiety;

R^(X2) is independently selected from H, C₁-C₈ alkyl, C₁-C₈ substitutedalkyl, C₆-C₂₀ aryl, C₆-C₂₀ substituted aryl, C₂-C₂₀ heteroaryl, andC₂-C₂₀ substituted heteroaryl, polyethyleneoxy, phosphonate, phosphate,a prodrug moiety, and a protecting group selected from the groupconsisting of benzyhydryl (CHPh₂), trialkylsilyl (R₃Si),2-trimethylsilylethyl, alkoxymethyl (CH₂OR), and ester (C(═O)R);

and the tautomers, salts, solvates, resolved enantiomers and purifieddiastereomers thereof.

In one aspect, the invention includes tricyclic compounds represented bythe following structure:

The compounds of the invention share a tricyclic scaffold and apotential active site or metal binding motif defined by the lower sideof the Formula above including the amide-type functionality, i.e.N—C(═X), of the left ring, the aromatic hydroxyl of the middle ring, andthe nitrogen of the right ring. The compounds of the invention havebinding functionality, e.g. nitrogen, hydroxyl, and X-carbonyl, in apre-organized configuration which may confer optimized inhibitoryproperties against HIV integrase.

A¹ and A² are each and independently a moiety forming a five, six, orseven membered ring. Q is N, substituted nitrogen (NR), CH, orsubstituted carbon. L is a bond or a linker connecting a ring atom of Arto N. X is O, S, NH, or substituted nitrogen (NR). Ar is a carbocycle,aryl or heteroaryl group. R is a substituent including H, alkyl, aryl,heteroaryl and substituted forms thereof, as well as polyethyleneoxy,phosphonate, phosphate, or a prodrug moiety. The 5 and 6 positions arerepresented in the structure above by Y and Z respectively. The chemicalbond between Y and Z may be a single bond, a double bond, or a bond withenolic, tautomeric character, depending on the substituent on Z, i.e. R¹or X. The Y and Z substructure is represented wherein:

The compounds of the invention may include prodrug moieties covalentlyattached at any site. The prodrug moiety may be a phosphonate group.

The invention also includes a pharmaceutical composition comprising atherapeutically effective amount of a compound of the invention, or apharmaceutically acceptable salt thereof, in combination with apharmaceutically acceptable diluent or carrier.

The invention also includes a pharmaceutical composition comprising atherapeutically effective amount of a compound of the invention, or apharmaceutically acceptable salt thereof in combination with atherapeutically effective amount of an AIDS treatment agent selectedfrom an HIV inhibitor agent, an anti-infective agent, and animmunomodulator. The HIV inhibitor agent may include an HIV-proteaseinhibitor, a nucleoside reverse transcriptase inhibitor, or anon-nucleoside reverse transcriptase inhibitor.

The invention also includes methods of preventing the proliferation ofHIV virus, treating AIDS, delaying the onset of AIDS or ARC symptoms,and generally inhibiting HIV integrase. The methods compriseadministering to a mammal infected with HIV (HIV positive) an amount ofa compound of the invention, in a therapeutically effective dose oradministration to inhibit the growth of HIV infected cells of themammal.

In another aspect of the invention, the activity of HIV integrase isinhibited by a method comprising the step of treating a sample suspectedof containing HIV virus with a compound or composition of the invention.

The invention also includes processes and novel intermediates disclosedherein which are useful for preparing compounds of the invention. Someof the compounds of the invention are useful to prepare other compoundsof the invention.

This invention also includes methods of increasing cellularaccumulation, bioavailability, or retention of drug compounds, thusimproving their therapeutic and diagnostic value, by administering aphosphonate prodrug form of a compound of the invention.

Another aspect of the invention provides a method for inhibiting theactivity of HIV integrase comprising the step of contacting a samplesuspected of containing HIV virus with the composition embodiments ofthe invention.

In other aspects, novel methods for the synthesis, analysis, separation,isolation, crystallization, purification, characterization, resolutionof isomers including enantiomers and diastereomers, and testing of thecompounds of this invention are provided.

DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS

Reference will now be made in detail to certain embodiments of theinvention, examples of which are illustrated in the accompanyingdescriptions, structure and formulas. While the invention will bedescribed in conjunction with the enumerated embodiments, it will beunderstood that they are not intended to limit the invention to thoseembodiments. On the contrary, the invention is intended to cover allalternatives, modifications, and equivalents, which may be includedwithin the scope of the present invention as defined by the claims.

DEFINITIONS

Unless stated otherwise, the following terms and phrases as used hereinare intended to have the following meanings:

The terms “phosphonate” and “phosphonate group” mean a functional groupor moiety within a molecule that comprises at least onephosphorus-carbon bond, and at least one phosphorus-oxygen double bond.The phosphorus atom is further substituted with oxygen, sulfur, andnitrogen substituents. These substituents may be part of a prodrugmoiety. As defined herein, “phosphonate” and “phosphonate group” includemolecules with phosphonic acid, phosphonic monoester, phosphonicdiester, phosphonamidate, phosphondiamidate, and phosphonthioatefunctional groups.

The term “prodrug” as used herein refers to any compound that whenadministered to a biological system generates the drug substance, i.e.active ingredient, as a result of spontaneous chemical reaction(s),enzyme catalyzed chemical reaction(s), photolysis, and/or metabolicchemical reaction(s). A prodrug is thus a covalently modified analog orlatent form of a therapeutically-active compound.

“Pharmaceutically acceptable prodrug” refers to a compound that ismetabolized in the host, for example hydrolyzed or oxidized, by eitherenzymatic action or by general acid or base solvolysis, to form anactive ingredient. Typical examples of prodrugs of the compounds of theinvention have biologically labile protecting groups on a functionalmoiety of the compound. Prodrugs include compounds that can be oxidized,reduced, aminated, deaminated, esterified, deesterified, alkylated,dealkylated, acylated, deacylated, phosphorylated, dephosphorylated,photolyzed, hydrolyzed, or other functional group change or conversioninvolving forming or breaking chemical bonds on the prodrug.

“Prodrug moiety” means a labile functional group which separates fromthe active inhibitory compound during metabolism, systemically, inside acell, by hydrolysis, enzymatic cleavage, or by some other process(Bundgaard, Hans, “Design and Application of Prodrugs” in Textbook ofDrug Design and Development (1991), P. Krogsgaard-Larsen and H.Bundgaard, Eds. Harwood Academic Publishers, pp. 113-19 1). Enzymeswhich are capable of an enzymatic activation mechanism with the prodrugcompounds of the invention include, but are not limited to, amidases,esterases, microbial enzymes, phospholipases, cholinesterases, andphosphases. Prodrug moieties can serve to enhance solubility, absorptionand lipophilicity to optimize drug delivery, bioavailability andefficacy. A “prodrug” is thus a covalently modified analog of atherapeutically-active compound.

Exemplary prodrug moieties include the hydrolytically sensitive orlabile acyloxymethyl esters —CH₂OC(═O)R⁹ and acyloxymethyl carbonates—CH₂OC(═O)OR⁹ where R⁹ is C₁-C₆ alkyl, C₁-C₆ substituted alkyl, C₆-C₂₀aryl or C₆-C₂₀ substituted aryl. The acyloxyalkyl ester was first usedas a prodrug strategy for carboxylic acids and then applied tophosphates and phosphonates by Farquhar et al (1983) J. Pharm. Sci. 72:324; also U.S. Pat. Nos. 4,816,570, 4,968,788, 5,663,159 and 5,792,756.In certain compounds of the invention, a prodrug moiety is part of aphosphonate group. Subsequently, the acyloxyalkyl ester was used todeliver phosphonic acids across cell membranes and to enhance oralbioavailability. A close variant of the acyloxyalkyl ester, thealkoxycarbonyloxyalkyl ester (carbonate), may also enhance oralbioavailability as a prodrug moiety in the compounds of the combinationsof the invention. An exemplary acyloxymethyl ester ispivaloyloxymethoxy, (POM) —CH₂OC(═O)C(CH₃)₃. An exemplary acyloxymethylcarbonate prodrug moiety is pivaloyloxymethylcarbonate (POC)—CH₂OC(═O)OC(CH₃)₃.

The phosphonate group may be a phosphonate prodrug moiety. The prodrugmoiety may be sensitive to hydrolysis, such as, but not limited to apivaloyloxymethyl carbonate (POC) or POM group. Alternatively, theprodrug moiety may be sensitive to enzymatic potentiated cleavage, suchas a lactate ester or a phosphonamidate-ester group. Exemplaryphosphonate prodrug moieties include by way of example and notlimitation groups of the structure A³.

Aryl esters of phosphorus groups, especially phenyl esters, are reportedto enhance oral bioavailability (DeLambert et al (1994) J. Med. Chem.37: 498). Phenyl esters containing a carboxylic ester ortho to thephosphate have also been described (Khamnei and Torrence, (1996) J. Med.Chem. 39:4109-4115). Benzyl esters are reported to generate the parentphosphonic acid. In some cases, substituents at the ortho-orpara-position may accelerate the hydrolysis. Benzyl analogs with anacylated phenol or an alkylated phenol may generate the phenoliccompound through the action of enzymes, e.g. esterases, oxidases, etc.,which in turn undergoes cleavage at the benzylic C—O bond to generatethe phosphoric acid and the quinone methide intermediate. Examples ofthis class of prodrugs are described by Mitchell et al (1992) J. Chem.Soc. Perkin Trans. I 2345; Brook et al WO 91/19721. Still other benzylicprodrugs have been described containing a carboxylic ester-containinggroup attached to the benzylic methylene (Glazier et al WO 91/1972 1).Thio-containing prodrugs are reported to be useful for tie intracellulardelivery of phosphonate drugs. These proesters contain an ethylthiogroup in which the thiol group is either esterified with an acyl groupor combined with another thiol group to form a disulfide.Deesterification or reduction of the disulfide generates the free thiointermediate which subsequently breaks down to the phosphoric acid andepisulfide (Puech et al (1993) Antiviral Res. 22: 155-174; Benzaria etal (1996) J. Med. Chem. 39: 4958). Cyclic phosphonate esters have alsobeen described as prodrugs of phosphorus-containing compounds (Erion etal, U.S. Pat. No. 6,312,662).

“Protecting group” refers to a moiety of a compound that masks or altersthe properties of a functional group or the properties of the compoundas a whole. The chemical substructure of a protecting group varieswidely. One function of a protecting group is to serve as intermediatesin the synthesis of the parental drug substance. Chemical protectinggroups and strategies for protection/deprotection are well known in theart. See: “Protective Groups in Organic Chemistry”, Theodora W. Greene(John Wiley & Sons, Inc., New York, 1991, which is incorporated hereinby reference. Protecting groups are often utilized to mask thereactivity of certain functional groups, to assist in the efficiency ofdesired chemical reactions, e.g. making and breaking chemical bonds inan ordered and planned fashion. Protection of functional groups of acompound alters other physical properties besides the reactivity of theprotected functional group, such as the polarity, lipophilicity(hydrophobicity), and other properties which can be measured by commonanalytical tools. Chemically protected intermediates may themselves bebiologically active or inactive.

Protected compounds may also exhibit altered, and in some cases,optimized properties in vitro and in vivo, such as passage throughcellular membranes and resistance to enzymatic degradation orsequestration. In this role, protected compounds with intendedtherapeutic effects may be referred to as prodrugs. Another function ofa protecting group is to convert the parental drug into a prodrug,whereby the parental drug is released upon conversion of the prodrug invivo. Because active prodrugs may be absorbed more effectively than theparental drug, prodrugs may possess greater potency in vivo than theparental drug. Protecting groups are removed either in vitro, in theinstance of chemical intermediates, or in viva, in the case of prodrugs.With chemical intermediates, it is not particularly important that theresulting products after deprotection, e.g. alcohols, be physiologicallyacceptable, although in general it is more desirable if the products arepharmacologically innocuous. Exemplary protecting groups include by wayof example and not limitation groups of the structure R^(X) other thanhydrogen.

Any reference to any of the compounds of the invention also includes areference to a physiologically acceptable salt thereof: Examples ofphysiologically acceptable salts of the compounds of the inventioninclude salts derived from an appropriate base, such as an alkali metal(for example, sodium), an alkaline earth (for example, magnesium),ammonium and NX₄ ⁺ (wherein X is C₁-C₄ alkyl). Physiologicallyacceptable salts of an hydrogen atom or an amino group include salts oforganic carboxylic acids such as acetic, benzoic, lactic, fumaric,tartaric, maleic, malonic, malic, isethionic, lactobionic and succinicacids; organic sulfonic acids, such as methanesulfonic, ethanesulfonic,benzenesulfonic and p-toluenesulfonic acids; and inorganic acids, suchas hydrochloric, sulfuric, phosphoric and sulfonic acids.Physiologically acceptable salts of a compound of an hydroxy groupinclude the anion of said compound in combination with a suitable cationsuch as Na⁺ and NX₄ ⁺ (wherein X is independently selected from H or aC₁-C₄ alkyl group).

For therapeutic use, salts of active ingredients of the compounds of theinvention will be physiologically acceptable, i.e. they will be saltsderived from a physiologically acceptable acid or base. However, saltsof acids or bases which are not physiologically acceptable may also finduse, for example, in the preparation or purification of aphysiologically acceptable compound. All salts, whether or not derivedform a physiologically acceptable acid or base, are within the scope ofthe present invention.

“Alkyl” is C₁-C₁₈ hydrocarbon containing normal, secondary, tertiary orcyclic carbon atoms. Examples are methyl (Me, —CH₃), ethyl (Et,—CH₂CH₃), 1-propyl (n-Pr, n-propyl, —CH₂CH₂CH₃), 2-propyl (i-Pr,i-propyl, —CH(CH₃)₂), 1-butyl (n-Bu, n-butyl, —CH₂CH₂CH₂CH₃),2-methyl-1-propyl (i-Bu, i-butyl, —CH₂CH(CH₃)₂), 2-butyl (s-Bu, s-butyl,—CH(CH₃)CH₂CH₃), 2-methyl-2-propyl (t-Bu, t-butyl, —C(C₃)₃), 1-pentyl(n-pentyl, —CH₂CH₂CH₂CH₂CH₃), 2-pentyl (—CH(CH₃)CH₂CH₂CH₃), 3-pentyl(—CH(CH₂CH₃)₂), 2-methyl-2-butyl (—C(CH₃)₂CH₂CH₃), 3-methyl-2-butyl(—CH(CH₃)CH(CH₃)₂), 3-methyl-1-butyl (—CH₂CH₂CH(CH₃)₂), 2-methyl-1-butyl(—CH₂CH(CH₃)CH₂CH₃), 1-hexyl (—CH₂CH₂CH₂CH₂CH₂CH₃), 2-hexyl(—CH(CH₃)CH₂CH₂CH₂CH₃), 3-hexyl (—CH(CH₂CH₃)(CH₂CH₂CH₃)),2-methyl-2-pentyl (—C(CH₃)₂CH₂CH₂CH₃), 3-methyl-2-pentyl(—CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl (—CH(CH₃)CH₂CH(CH₃)₂),3-methyl-3-pentyl (—C(CH₃)(CH₂CH₃)₂), 2-methyl-3-pentyl(—CH(CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl (—C(CH₃)₂CH(CH₃)₂),3,3-dimethyl-2-butyl (—CH(CH₃)C(CH₃)₃.

“Alkenyl” is C₂-C₁₈ hydrocarbon containing normal, secondary, tertiaryor cyclic carbon atoms with at least one site of unsaturation, i.e. acarbon-carbon, sp² double bond. Examples include, but are not limitedto: ethylene or vinyl (—CH═CH₂), allyl (—CH₂CH═CH₂), cyclopentenyl(—C₅H₇), and 5-hexenyl (—CH₂ CH₂CH₂CH₂CH═CH₂)

“Alkynyl” is C₂-C₁₈ hydrocarbon containing normal, secondary, tertiaryor cyclic carbon atoms with at least one site of unsaturation, i.e. acarbon-carbon, sp triple bond. Examples include, but are not limited to:acetylenic (—C≡CH) and propargyl (—CH₂C≡CH),

The terms “alkylene” and “akyldiyl” each refer to a saturated, branchedor straight chain or cyclic hydrocarbon radical of 1-18 carbon atoms,and having two monovalent radical centers derived by the removal of twohydrogen atoms from the same or two different carbon atoms of a parentalkane. Typical alkylene radicals include, but are not limited to:methylene (—CH₂—) 1,2-ethyl (—CH₂CH₂—), 1,3-propyl (—CH₂CH₂CH₂—),1,4-butyl (—CH₂CH₂CH₂CH₂—), and the like.

37 Alkenylene” refers to an unsaturated, branched or straight chain orcyclic hydrocarbon radical of 2-18 carbon atoms, and having twomonovalent radical centers derived by the removal of two hydrogen atomsfrom the same or two different carbon atoms of a parent alkene, i.e.double carbon-carbon bond moiety. Typical alkenylene radicals include,but are not limited to: 1,2-ethylene (—CH═CH—).

“Alkynylene” refers to an unsaturated, branched or straight chain orcyclic hydrocarbon radical of 2-18 carbon atoms, and having twomonovalent radical centers derived by the removal of two hydrogen atomsfrom the same or two different carbon atoms of a parent alkyne, i.e.triple carbon-carbon bond moiety. Typical alkynylene radicals include,but are not limited to: acetylene (—C≡C—), propargyl (—CH₂C≡C—), and4-pentynyl (—CH₂CH₂CH₂C≡CH—).

“Aryl” means a monovalent aromatic hydrocarbon radical of 6-20 carbonatoms derived by the removal of one hydrogen atom from a single carbonatom of a parent aromatic ring system. Typical aryl groups include, butare not limited to, radicals derived from benzene, substituted benzene,naphthalene, anthracene, biphenyl, and the like.

“Heteroaryl” means a monovalent aromatic radical of one or more carbonatoms and one or more atoms selected from N, O, S, or P, derived by theremoval of one hydrogen atom from a single atom of a parent aromaticring system. Heteroaryl groups may be a monocycle having 3 to 7 ringmembers (2 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O,P, and S) or a bicycle having 7 to 10 ring members (4 to 9 carbon atomsand 1 to 3 heteroatoms selected from N, O, P, and S). Heteroarylbicycles have 7 to 10 ring atoms (6 to 9 carbon atoms and 1 to 2heteroatoms selected from N, O, and S) arranged as a bicyclo [4,5],[5,5], [5,6], or [6,6] system; or 9 to 10 ring atoms (8 to 9 carbonatoms and 1 to 2 hetero atoms selected from N and S) arranged as abicyclo [5,6] or [6,6] system. The heteroaryl group may be bonded to thedrug scaffold through a carbon, nitrogen, sulfur, phosphorus or otheratom by a stable covalent bond.

Heteroaryl groups include, for example: pyridyl, dihydropyridyl isomers,pyridazinyl, pyrimidinyl, pyrazinyl, s-triazinyl, oxazolyl, imidazolyl,thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, furanyl, thiofuranyl,thienyl, and pyrrolyl.

“Arylalkyl” refers to an acyclic alkyl radical in which one of thehydrogen atoms bonded to a carbon atom, typically a terminal or sp³carbon atom, is replaced with an aryl radical. Typical arylalkyl groupsinclude, but are not limited to, benzyl, 2-phenylethen-1-yl,2-phenylethen-1-yl, naphthylmethyl, 2-naphthylethan-1-yl,2-naphthylethen-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl and thelike. The arylalkyl group comprises 6 to 20 carbon atoms, e.g. the alkylmoiety, including alkanyl, alkenyl or alkynyl groups, of the arylalkylgroup is 1 to 6 carbon atoms and the aryl moiety is 5 to 14 carbonatoms.

Substituted substituents such as “substituted alkyl”, “substitutedaryl”, “substituted heteroaryl” and “substituted arylalkyl” mean alkyl,aryl, and arylalkyl respectively, in which one or more hydrogen atomsare each independently replaced with a substituent. Typical substituentsinclude, but are not limited to, —X, —R, —O⁻, —OR, —SR, —S⁻, —NR₂, —NR₃,═NR, —CX₃, —CN, —OCN, —SCN, —N═C═O, —NCS, —NO, —NO₂, ═N₂, —N₃, NC(═O)R,—C(═O)R, —C(═O)NRR —S(═O)₂O⁻, —S(═O)₂OH, —S(═O)₂R, —OS(═O)₂OR,—S(═O)₂NR, —S(═O)R, —OP(═O)O₂RR, —P(═O)O₂RR, —P(═O)(O⁻)₂, —P(═O)(OH)₂,—C(═O)R, —C(═O)X, —C(S)R, —C(O)OR, —C(O)O⁻, —C(S)OR, —C(O)SR, —C(S)SR,—C(O)NRR, —C(S)NRR, —C(NR)NRR, where each X is independently a halogen:F, Cl, Br, or I; and each R is independently —H, alkyl, aryl,heterocycle, protecting group or prodrug moiety. Alkylene, alkenylene,and alkynylene groups may also be similarly substituted.

“Heterocycle” means a saturated, unsaturated or aromatic ring systemincluding at least one N, O, S, or P. Heterocycle thus includeheteroaryl groups. Heterocycle as used herein includes by way of exampleand not limitation these heterocycles described in Paquette, Leo A.“Principles of Modern Heterocyclic Chemistry” (W. A. Benjamin, New York,1968), particularly Chapters 1, 3, 4, 6, 7, and 9; “The Chemistry ofHeterocyclic Compounds, A series of Monographs” (John Wiley & Sons, NewYork, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28;Katritzky, Alan R., Rees, C. W. and Scriven, E. “ComprehensiveHeterocyclic Chemistry” (Pergamon Press, 1996); and J. Am. Chem. Soc.(1960) 82:5566.

Examples of heterocycles include by way of example and not limitationpyridyl, dihydroypyridyl, tetrahydropyridyl(piperidyl), thiazolyl,tetrahydrothiophenyl, sulfur oxidized tetrahydrothiophenyl, pyrimidinyl,furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl,benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl,isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl,2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, bis-tetrahydrofuranyl,tetrahydropyranyl, bis-tetrahydropyranyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl,azocinyl, triazinyl, 6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl,thienyl, thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl,phenoxathinyl, 2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl,pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, 1H-indazoly, purinyl,4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl,quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl,β-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl,chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl,piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl,oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl,and isatinoyl.

One embodiment of the bis-tetrahydrofuranyl group is:

By way of example and not limitation, carbon bonded heterocycles arebonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2,3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan,tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole,position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4,or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of anaziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6,7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of anisoquinoline. Still more typically, carbon bonded heterocycles include2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl,4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl,4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl,5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl.

By way of example and not limitation, nitrogen bonded heterocycles arebonded at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine,2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline,3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline,piperidine, piperazine, indole, indoline, 1H-indazole, position 2 of aisoindole, or isoindoline, position 4 of a morpholine, and position 9 ofa carbazole, or β-carboline. Still more typically, nitrogen bondedheterocycles include 1-aziridyl, 1-azetedyl, 1-pyrrolyl, 1-imidazolyl,1-pyrazolyl, and 1-piperidinyl.

“Carbocycle” means a saturated, unsaturated or aromatic ring systemhaving 3 to 7 carbon atoms as a monocycle or 7 to 12 carbon atoms as abicycle. Monocyclic carbocycles have 3 to 6 ring atoms, still moretypically 5 or 6 ring atoms. Bicyclic carbocycles have 7 to 12 ringatoms, e.g. arranged as a bicyclo [4,5], [5,5], [5,6] or [6,6] system,or 9 or 10 ring atoms arranged as a bicyclo [5,6] or [6,6] system.Examples of monocyclic carbocycles include cyclopropyl, cyclobutyl,cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl,cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl,phenyl, spiryl and naphthyl. Carbocycle thus includes some aryl groups.

“Linker” or “link” means a chemical moiety comprising a covalent bond ora chain of atoms that covalently attaches a phosphonate group to a drug.Linkers include L interposed between Ar and the nitrogen of thetricyclic compounds of the invention. The structures herein may refer tolinkers as “link” or “L”. Linkers may also be interposed between aphosphorus-containing A³ group and the R¹, R², R³, or R⁴ position of thecompounds of the invention. Linkers include, but are not limited tomoieties such as O, S, NR, N—OR, C₁-C₁₂ alkylene, C₁-C₁₂ substitutedalkylene, C₂-C₁₂ alkenylene, C₂-C₁₂ substituted alkenylene, C₂-C₁₂alkynylene, C₂-C₁₂ substituted alkynylene, C(═O)NH, C(═O), S(═O)₂,C(═O)NH(CH₂)_(n), and (CH₂CH₂O)_(n), where n may be 1, 2, 3, 4, 5, or 6.Linkers also include repeating units of alkyloxy (e.g. polyethylenoxy,PEG, polymethyleneoxy) and alkylamino (e.g. polyethyleneamino,Jeffamine™); and diacid ester and amides including succinate,succinamide, diglycolate, malonate, and caproamide.

The term “chiral” refers to molecules which have the property ofnon-superimposability of the mirror image partner, while the term“achiral” refers to molecules which are superimposable on their mirrorimage partner.

The term “stereoisomers” refers to compounds which have identicalchemical constitution, but differ with regard to the arrangement of theatoms or groups in space.

“Diastereomer” refers to a stereoisomer with two or more centers ofchirality and whose molecules are not mirror images of one another.Diastereomers have different physical properties, e.g. melting points,boiling points, spectral properties, and reactivities. Mixtures ofdiastereomers may separate under high resolution analytical proceduressuch as electrophoresis and chromatography.

“Enantiomers” refer to two stereoisomers of a compound which arenon-superimposable mirror images of one another.

Stereochemical definitions and conventions used herein generally followS. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984)McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S.,Stereochemistry of Organic Compounds (1994) John Wiley & Sons, Inc., NewYork. Many organic compounds exist in optically active forms, i.e., theyhave the ability to rotate the plane of plane-polarized light. Indescribing an optically active compound, the prefixes D and L or R and Sare used to denote the absolute configuration of the molecule about itschiral center(s). The prefixes d and I or (+) and (−) are employed todesignate the sign of rotation of plane-polarized light by the compound,with (−) or l meaning that the compound is levorotatory. A compoundprefixed with (+) or d is dextrorotatory. For a given chemicalstructure, these stereoisomers are identical except that they are mirrorimages of one another. A specific stereoisomer may also be referred toas an enantiomer, and a mixture of such isomers is often called anenantiomeric mixture. A 50:50 mixture of enantiomers is referred to as aracemic mixture or a racemate, which may occur where there has been nostereoselection or stereospecificity in a chemical reaction or process.The terms “racemic mixture” and “racemate” refer to an equimolar mixtureof two enantiomeric species, devoid of optical activity.

HIV-Integrase Inhibitor Compounds

Novel tricyclic compounds with inhibitory activity against HIV integraseare described, including any pharmaceutically acceptable salts thereof.

In one aspect, the invention comprises a compound having the structure:

wherein:

A¹ and A² are independently selected from O, S, NR, C(R²)₂, CR²OR,CR²OC(═O)R, C(═O), C(═S), CR²SR, C(═NR), C(R²)₂—C(R³)₂, C(R²)═C(R³),C(R²)₂—O, NR—C(R³)₂, N═C(R³), N═N, SO₂—NR, C(═O)C(R³)₂, C(═O)NR,C(R²)₂—C(R³)₂—C(R³)₂, C(R²)═C(R³)—C(R³)₂, C(R²)C(═O)NR, C(R²)C(═S)NR,C(R²)═N—C(R³)₂, C(R²)═N—NR, and N═C(R³)—NR;

Q is N, ⁻NR, or CR⁴;

L is selected from a bond, O, S, S—S, S(═O), S(═O)₂, S(═O)₂NR, NR, N—OR,C₁-C₁₂ alkylene, C₁-C₁₂ substituted alkylene, C₂-C₁₂ alkenylene, C₂-C₁₂substituted alkenylene, C₂-C₁₂ alkynylene, C₂-C₁₂ substitutedalkynylene, C(═O)NH, OC(═O)NH, NHC(═O)NH, C(═O), C(═O)NH(CH₂)_(n), or(CH₂CH₂O)_(n), where n may be 1, 2, 3, 4, 5, or 6;

X is selected from O, S, NH, NR, N—OR, N—NR₂, N—CR₂OR and N—CR₂NR₂;

Ar is selected from C₃-C₁₂ carbocycle, C₃-C₁₂ substituted carbocycle,C₆-C₂₀ aryl, C₆-C₂₀ substituted aryl, C₂-C₂₀ heteroaryl, and C₂-C₂₀substituted heteroaryl;

R¹ R², R³ and R⁴ are each independently selected from H, F, Cl, Br, I,OH, —NH₂, —NH₃ ⁺, —NHR, —NR₂, —NR₃ ⁺, C₁-C₈ alkylhalide, carboxylate,sulfate, sulfamate, sulfonate, 5-7 membered ring sultam, C₁-C₈alkylsulfonate, C₁-C₈ alkylamino, 4-dialkylaminopyridinium, C₁-C₈alkylhydroxyl, C₁-C₈ alkylthiol, —SO₂R, —SO₂Ar, —SOAr, —SAr, —SO₂NR₂,—SOR, —CO₂R, —C(═)NR₂, 5-7 membered ring lactam, 5-7 membered ringlactone, —CN, —N₃, —NO₂, C₁-C₈ alkoxy, C₁-C₈ trifluoroalkyl, C₁-C₈alkyl, C₁-C₈ substituted alkyl, C₃-C₁₂ carbocycle, C₃-C₁₂ substitutedcarbocycle, C₆-C₂₀ aryl, C₆-C₂₀ substituted aryl, C₂-C₂₀ heteroaryl, andC₂-C₂₀ substituted heteroaryl polyethyleneoxy, phosphonate, phosphate,and a prodrug moiety;

when taken together on a single carbon, two R² or two R³ may form aspiro ring; and

R is independently selected from H, C₁-C₈ alkyl, C₁-C₈ substitutedalkyl, C₆-C₂₀ aryl, C₆-C₂₀ substituted aryl, C₂-C₂₀ heteroaryl andC₂-C₂₀ substituted heteroaryl, polyethyleneoxy, phosphonate, phosphate,and a prodrug moiety;

R^(X2) is independently selected from H, C₁-C₈ alkyl, C₁-C₈ substitutedalkyl, C₆-C₂₀ aryl, C₆-C₂₀ substituted aryl, C₂-C₂₀ heteroaryl, andC₂-C₂₀ substituted heteroaryl, polyethyleneoxy, phosphonate, phosphate,a prodrug, a pharmaceutically acceptable prodrug, a prodrug moiety, aprotecting group, and a phosphonate prodrug moiety;

and the salts, solvates, resolved enantiomers and purified diastereomersthereof;

with the proviso that when Y=Z is C═C(OH), X is O, A¹ is C(═O), A² isC(R²)═C(R³), and Q is CH, then L is not a bond.

In one aspect, the invention is a compound having the structure:

or a salt thereof,

wherein:

A¹ and A² are independently selected from O, S, NR, C(R²)₂, CR²OR,CR²OC(═O)R, C(═O), C(═S), CR²SR, C(═NR), C(R²)₂—C(R³)₂, C(R²)═C(R³),NR—C(R³)₂, N═C(R³), N═N, SO₂—NR, C(═O)C(R³)₂, C(═O)NR,C(R²)₂—C(R³)₂—C(R³)₂, C(R²═C(R³)—C(R³)₂, C(R²)C(═O)NR, C(R²)C(═S)NR,C(R²)═N—C(R³)₂, C(R²)═N—NR, and N═C(R³)—NR;

Q is N, ⁺NR, or CR⁴;

L is selected from a bond, O, S, S—S, S(═O), S(═O)₂, S(═O)₂NR, NR, N—OR,C₁-C₁₂ alkylene, C₁-C₁₂ substituted alkylene, C₂-C₁₂ alkenylene, C₂-C₁₂substituted alkenylene, C₂-C₁₂ alkynylene, C₂-C₁₂ substitutedalkynylene, C(═O)NH, OC(═O)NH, NHC(═O)NH, C(═O), C(═O)NH(CH₂)_(n), or(CH₂CH₂O)_(n), where n may be 1, 2, 3, 4, 5, or 6;

X is selected from O, S, NH, NR, N—OR, N—NR₂, N—CR₂OR and N—CR₂NR₂;

Ar is selected from C₃-C₁₂ carbocycle, C₃-C₁₂ substituted carbocycle,C₆-C₂₀ aryl, C₆-C₂₀ substituted aryl, C₂-C₂₀ heteroaryl, and C₂-C₂₀substituted heteroaryl;

R¹, R², R³ and R⁴ are each independently selected from H, F, Cl, Br, I,OH, —NH₂, —NH₃ ⁺, —NHR, —NR₂, —NR₃ ⁺, C₁-C₈ alkylhalide, carboxylate,sulfate, sulfamate, sulfonate, 5-7 membered ring sultam, C₁-C₈alkylsulfonate, C₁-C₈ alkylamino, 4-dialkylaminopyridinium, C₁-C₈alkylhydroxyl, C₁-C₈ alkylthiol, —SO₂R, —SO₂Ar, —SOAr, —SAr, —SO₂NR₂,—SOR, —CO₂R, —C(═O)NR₂, 5-7 membered ring lactam, 5-7 membered ringlactone, —CN, —N₃, —NO₂, C₁-C₈ alkoxy, C₁-C₈ trifluoroalkyl, C₁-C₈alkyl, C₁-C₈ substituted alkyl, C₃-C₁₂ carbocycle, C₃-C₁₂ substitutedcarbocycle, C₆-C₂₀ aryl, C₆-C₂₀ substituted aryl, C₂-C₂₀ heteroaryl, andC₂-C₂₀ substituted heteroaryl, polyethyleneoxy, phosphonate, phosphate,and a prodrug moiety;

when taken together on a single carbon, two R² or two R³ may form aspiro ring;

R is independently selected from H, C₁-C₈ alkyl, C₁-C₈ substitutedalkyl, C₆-C₂₀ aryl, C₆-C₂₀ substituted aryl, C₂-C₂₀ heteroaryl, andC₂-C₂₀ substituted heteroaryl, polyethyleneoxy, phosphonate, phosphate,and a prodrug; and

P is a protecting group selected from benzyhydryl (CHPh₂), trialkylsilyl(R₃Si), 2-trimethylsiloxyethyl, alkoxynethyl (CH₂OR), and ester(C(═O)R).

In one aspect, the compounds are pre-organized with constrainedconformations that include an active form for inhibition of nuclearintegration of reverse-transcribed HIV DNA. The invention includestricyclic compounds represented by the following structure:

A¹ and A² are each and independently any moiety forming a five, six, orseven membered ring. A¹ and A² may be independently selected from O, S,NR, C(R²)₂, CR²OR, CR²OC(═O)R, C(═O), C(S), CR²SR, C(═NR),C(R²)₂—C(R³)₂, —C(R²)═C(R³), C(R²)₂—O, NR—C(R³)₂, N═C(R³), N═N, SO₂—NR,C(═O)C(R³)₂, C(═O)NR, C(R²)₂—C(R³)₂—C(R³)₂, C(R²)═C(R³)—C(R³)₂,C(R²)C(═O)NR, C(R²)C(═S)NR, C(R²)═N—C(R³)₂, C(R²)═N—NR, and N═C(R³)—NR.When taken together on a single carbon, two R² or two R³ may form aspiro ring.

Q is N, ⁻NR, or CR⁴.

L is a bond or any linker which covalently attaches the Ar group to thetricyclic scaffold. For example, L may be a bond, O, S, S—S (disulfide),S(═O) (sulfoxide), S(═O)₂ (sulfone), S(═O)₂NR (sulfonamide), NR, N—OR,C₁-C₁₂ alkylene, C₁-C₁₂ substituted alkylene, C₂-C₁₂ alkenylene, C₂-C₁₂substituted alkenylene, C₂-C₁₂ alkynylene, C₂-C₁₂ substitutedalkynylene, C(═O)NH, OC(═O)NH, NHC(═O)NH, C(═O), C(═O)NH(CH₂)_(n), or(CH₂CH₂O)_(n), where n may be 1, 2, 3, 4, 5, or 6.

Substituted alkylene, substituted alkyenylene, substituted alkynylene,substituted aryl, and substituted heteroaryl are independentlysubstituted with one or more substituents selected from F, Cl, Br, I,OH, amino (—NH₂), ammonium (—NH₃ ⁺), alkylamino, dialkylamino,trialkylammonium, C₁-C₈ alkyl, C₁-C₈ alkylhalide, carboxylate, sulfate,sulfamate, sulfonate, 5-7 membered ring sultam, C₁-C₈ alkylsulfonate,C₁-C₈ alkylamino, 4-dialkylaminopyridinium, C₁-C₈ alkylhydroxyl, C₁-C₈alkylthiol, alkylsulfone (—SO₂R), arylsulfone (—SO₂Ar), arylsulfoxide(—SOAr), arylthio (—SAr), sulfonamide (—SO₂NR₂), alkylsulfoxide (—SOR),ester (—CO₂R), amido (—C(═O)NR₂), 5-7 membered ring lactam, 5-7 memberedring lactone, nitrile (—CN), azido (—N₃), nitro (—NO₂), C₁-C₈ alkoxy(—OR), C₁-C₈ alkyl, C₁-C₈ substituted alkyl, C₆-C₂₀ aryl, C₆-C₂₀substituted aryl, C₂-C₂₀ heteroaryl, and C₂-C₂₀ substituted heteroaryl,phosphonate, phosphate, polyethyleneoxy, and a prodrug moiety.

X may be O, S, NH, NR, N—OR, N—NR₂, N—CR₂OR or N—CR₂NR₂.

Ar groups may be any saturated, unsaturated or aromatic ring or ringsystem comprising a mono- or bicyclic carbocycle or heterocycle, e.g. 3to 12 ring atoms. The rings are saturated when containing 3 ring atoms,saturated or mono-unsaturated when containing 4 ring atoms, saturated,or mono- or di-unsaturated when containing 5 ring atoms, and saturated,mono- or di-unsaturated, or aromatic when containing 6 ring atoms.

For example, Ar may be C₃-C₁₂ carbocycle, C₃-C₁₂ substituted carbocycle,C₆-C₂₀ aryl, C₆-C₂₀ substituted aryl, C₂-C₂₀ heteroaryl, or C₂-C₂₀substituted heteroaryl.

Exemplary embodiments of C₆-C₂₀ substituted aryl groups includehalo-substituted phenyl such as 4-fluorophenyl, 4-chlorophenyl,4-trifluoromethyl, 2-amide phenyl, 3,5-dichlorophenyl, and3,5-difluorophenyl.

Ar groups include substituted phenyl groups such as, but not limited to:

Other examples of substituted phenyl groups include:

where a wavy line

in any orientation, indicates the covalent attachment site to L.

Ar groups also include disubstituted phenyl groups such as, but notlimited to:

where n is 1 to 6.

Ar groups also include carbocycles such as, but not limited to:

Ar groups also include phenyl and substituted phenyl fused to acarbocycle to form groups including:

R¹, R², R³ and R⁴, and substituents of Ar, may independently be H, F,Cl, Br, I, OH, amino (—NH₂), ammonium (—NH₃ ⁺), alkylamino,dialkylamino, trialkylammonium, C₁-C₈ alkylhalide, carboxylate, sulfate,sulfamate, sulfonate, 5-7 membered ring sultam, C₁-C₈ alkylsulfonate,C₁-C₈ alkylamino, 4-dialkylaminopyridinium, C₁-C₈ alkylhydroxyl, C₁-C₈alkylthiol, alkylsulfone (—SO₂R), arylsulfone (—SO₂Ar), arylsulfoxide(—SOAr), arylthio (—SAr), sulfonamide (—SO₂NR₂), alkylsulfoxide (—SOR),ester (—CO₂R), amido (—C(═O)NR₂), 5-7 membered ring lactam, 5-7 memberedring lactone, nitrile (—CN), azido (—N₃), nitro (—NO₂), C₁-C₈ alkoxy(—OR), C₁-C₈ trifluoroalkyl, C₁-C₈ alkyl, C₁-C₈ substituted alkyl,C₃-C₁₂ carbocycle, C₃-C₁₂ substituted carbocycle, C₆-C₂₀ aryl, C₆-C₂₀substituted aryl, C₂-C₂₀ heteroaryl, and C₂-C₂₀ substituted heteroaryl,phosphonate, phosphate, polyethyleneoxy, and a prodrug moiety.

R¹, R², R³, and R⁴ also include: —OC(═O)OR, —OC(═O)NR₂, —OC(═S)NR₂,—OC(═O)NRNR₂, —OC(═O)R, —C(═O)OR, —C(═O)NR₂, —C(═O)NRNR₂, —C(═O)R,—OSO₂NR₂ (sulfamate), —NR₂, —NRSO₂R, —NRC(═S)NR₂, —SR, —S(O)R, —SO₂R,—SO₂NR₂ (sulfonamide), —OSO₂R (sulfonate), —P(═O)(OR)₂, —P(═O)(OR)(NR₂),—P(═O)(NR₂)₂, —P(═S)(OR)₂, —P(═S)(OR)(NR₂), —P(═S)(NR₂)₂, and includingprodrug substituted forms thereof.

Exemplary embodiments of R¹, R², R³, and R⁴ include the structures:

where the wavy line indicates the point of covalent attachment on thetricyclic structure.

R may be independently selected from H, C₁-C₈ alkyl, C₁-C₈ substitutedalkyl, C₆-C₂₀ aryl, C₆-C₂₀ substituted aryl, C₂-C₂₀ heteroaryl, C₂-C₂₀substituted heteroaryl, polyethyleneoxy, phosphonate, phosphate, and aprodrug moiety. Two R groups may form a ring, such as when the two Rgroups are bonded to a nitrogen atom and form a ring such as aziridinyl,azetidinyl, pyrrolidinyl, pyrazinyl, imidazolyl, piperidyl, piperazinyl,pyridinium, or morpholino.

The following embodiments of A¹ and A² in the compounds of the inventioninclude but are not limited to the following structures. Variousembodiments of A¹ form 5-membered rings in the exemplary structures:

Various embodiments of A¹ form 6-membered rings in the exemplarystructures:

Various embodiments of A¹ form 7-membered rings in the exemplarystructures

Various embodiments of A² form 5-membered rings in the exemplarystructures:

Other various embodiments of A² form 6-membered rings in the exemplarystructures:

Other various embodiments of A² form 7-membered rings in the exemplarystructures:

Compounds of the invention include Formulas I-IV, represented by thefollowing structures:

Formula I compounds thus include the following succinimide structure:

Embodiments of Formula I also include Ia-c where A is CH₂, CH₂CH₂, andCH₂CH₂CH₂, respectively:

Where A forms a seven-membered ring, the 7 membered ring may becomprised of a second amide group, as shown by exemplary Formula Id:

One aspect of the invention includes compounds with a cyclic imidegroup, e.g. 5,9-dihydroxy-pyrrolo[3,4-g]quinoline-6,8-dione (Myers, etal U.S. Pat. No. 5,252,560; Robinson, U.S. Pat. No. 5,854,275), where Ais C(═O) and X is O, as in formula Ie.

Along with other compounds of the invention, the cyclic imide group ofFormula Ie provides functionality which may be in a pre-organized statefor optimized HIV integrase inhibition relative to compounds without thecyclic imide group (Anthony, et al WO 02/30931; Zhuang, et al “Designand synthesis of 8-hydroxy-1,6-naphthyridines as novel HIV-1 integraseinhibitors” Interscience Conference on Antimicrobial Agents andChemotherapy, San Diego, Calif., Sep. 27-30, 2002).

Formula Ia compounds include the following amide structure:

R¹, R², R³, or R⁴ may independently comprise a phosphonate group orphosphonate prodrug moiety. A tricyclic integrase inhibitor compound ofthe invention may include one or more phosphonate group or phosphonateprodrug moiety. For example, R¹, R², R³, or R⁴ may comprise thestructure A³, where A³ is:

Y¹ is independently O, S, N(R^(x)), N(O)(R^(x)), N(OR^(x)),N(O)(OR^(x)), or N(N(R^(x))₂.

Y² is independently a bond, O, N(R^(x)), N(O)(R^(x)), N(OR^(x)),N(O)(OR^(x)), N(N(R^(x))₂), —S(═O)-(sulfoxide), —S(═O)₂-(sulfone),—S-(sulfide), or —S—S-(disulfide).

M2 is 0, 1 or 2.

M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,or 12.

M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12.

R^(y) is independently H, C₁-C₆ alkyl, C₁-C₆ substituted alkyl, aryl,substituted aryl, or a protecting group. Alternatively, taken togetherat a carbon atom, two vicinal R^(y) groups form a ring, i.e. a spirocarbon. The ring may be all carbon atoms, for example, cyclopropyl,cyclobutyl, cyclopentyl, or cyclohexyl, or alternatively, the ring maycontain one or more heteroatoms, for example, piperazinyl, piperidinyl,pyranyl, or tetrahydrofuryl.

R^(x) is independently H, C₁-C₆ alkyl, C₁-C₆ substituted alkyl, C₆-C₂₀aryl, C₆-C₂₀ substituted aryl, or a protecting group, or the formula:

M1a, M1c, and M1d are independently 0 or 1.

M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.

A linker may be interposed between positions R¹, R², R³ or R⁴ andsubstituent A³. The linker may be O, S, NR, N—OR, C₁-C₁₂ alkylene,C₁-C₁₂ substituted alkylene, C₂-C₁₂ alkenylene, C₂-C₁₂ substitutedalkenylene, C₂-C₁₂ alkynylene, C₂-C₁₂ substituted alkynylene, C(═O)NH,C(═O), S(═O)₂, C(═O)NH(CH₂)_(n), and (CH₂CH₂O)_(n), where n may be 1, 2,3, 4, 5, or 6. Linkers may also be repeating units of alkyloxy (e.g.polyethylenoxy, PEG, polymethyleneoxy) and alkylamino (e.g.polyethyleneamino, Jeffamine™); and diacid ester and amides includingsuccinate, succinamide, diglycolate, malonate, and caproamide. Forexample, the linker may comprise propargyl, urea, or alkoxy groups inthe exemplary structures:

Embodiments of A³ include where M2 is 0, such as:

and where M12b is 1, Y¹ is oxygen, and Y^(2b) is independently oxygen(O) or nitrogen (N(R^(x))) such as:

An embodiment of A³ includes:

where W⁵ is a carbocycle such as phenyl or substituted phenyl, andY^(2c) is independently O, N(R^(y)) or S. For example, R¹ may be H and nmay be 1.

W⁵ also includes, but is not limited to, aryl and heteroaryl groups suchas:

Another embodiment of A³ includes:

Such embodiments include:

where Y^(2b) is O or N(R^(x)); M12d is 1, 2, 3, 4, 5, 6, 7 or 8; R¹ is Hor C₁-C₆ alkyl; and the phenyl carbocycle is substituted with 0 to 3 R²groups where R² is C₁-C₆ alkyl or substituted alkyl. Such embodiments ofA³ include phenyl phosphonamidate amino acid, e.g. alanate esters andphenyl phosphonate-lactate esters:

Embodiments of R^(x) include esters, carbamates, carbonates, thioesters,amides, thioamides, and urea groups:

The compounds of the invention may also include one or more prodrugmoieties located as a covalently-attached substituent at any location orsite, e.g. Ar, L, X, A, R¹, R², R³, R⁴, or the 9-hydroxyl. Onesubstituent which may be modified as a prodrug moiety is a phosphonate,phosphate, phosphinate or other phosphorus functionality (Oliyai et alPharmaceutical Res. (1999) 16:1687-1693; Krise, J. and Stella, V. Adv.Drug Del. Reviews (1996) 19:287-310; Bischofberger et al, U.S. Pat. No.5,798,340). Prodrug moieties of phosphorus functionality serve to maskanionic charges and decrease polarity. The phosphonate prodrug moietymay be an ester (Oliyai, et al Intl. Jour. Pharmaceutics (1999)179:257-265), e.g. POC and POM (pivaloyloxymethyl, Yuan, et alPharmaceutical Res. (2000) 17:1098-1 103), or amidate which separatesfrom the integrase inhibitor compound in vivo or by exposure in vitro tobiological conditions, e.g. cells, tissue isolates. The separation maybe mediated by general hydrolytic conditions, oxidation, enzymaticaction or a combination of steps.

Compounds of the invention bearing one or more prodrug moieties mayincrease or optimize the bioavailability of the compounds as therapeuticagents. For example, bioavailability after oral administration may bepreferred and depend on resistance to metabolic degradation in thegastrointestinal tract or circulatory system, and eventual uptake insidecells. Prodrug moieties are considered to confer said resistance byslowing certain hydrolytic or enzymatic metabolic processes. Lipophilicprodrug moieties may also increase active or passive transport of thecompounds of the invention across cellular membranes (Darby, G.Antiviral Chem. & Chemotherapy (1995) Supp. 1, 6:54-63).

R^(X2) is independently selected from H, C₁-C₈ alkyl, C₁-C₈ substitutedalkyl, C₆-C₂₀ aryl, C₆-C₂₀ substituted aryl, C₂-C₂₀ heteroaryl, andC₂-C₂₀ substituted heteroaryl, polyethyleneoxy, phosphonate, phosphate,a prodrug, a pharmaceutically acceptable prodrug, a prodrug moiety, aprotecting group, and a phosphonate prodrug moiety; preferably H, aprodrug or a protecting group; more preferably, H or a prodrug; morepreferably yet R^(X2) is H.

Exemplary embodiments of the invention includes phosphonamidate andphosphonamidate (collectively “amidate”) prodrug compounds. Generalformulas for phosphonamidate and phosphonamidate prodrug moietiesinclude:

The phosphorus atom of the phosphonamidate group is bonded to a carbonatom. The nitrogen substituent R⁵ may include an ester, an amide, or acarbamate functional group. For example, R⁵ may be —CR₂C(═O)OR′ where R′is H, C₁-C₆ alkyl, C₁C₆ substituted alkyl, C₆-C₂₀ aryl, C₆-C₂₀substituted aryl, C₂-C₂₀ heteroaryl, or C₂-C₂₀ substituted heteroaryl.

Exemplary embodiments of phosphonamidate and phosphonamidate prodrugsinclude:

wherein R⁵ is —CR₂CO₂R⁷ where R⁶ and R⁷ are independently H or C₁C₈alkyl.

The nitrogen atom may comprise an amino acid residue within the prodrugmoiety, such as a glycine, alanine, or valine ester (e.g. valacyclovir,see: Beauchamp, et al Antiviral Chem. Chemotherapy (1992) 3:157-164),such as the general structure:

where R′ is the amino acid side-chain, e.g. H, CH₃, CH(CH₃)₂, etc.

An exemplary embodiment of a phosphonamidate prodrug moiety is:

Another embodiment of the invention is directed toward an HIV integraseinhibitor tricyclic compound of the invention which is capable ofaccumulating in human PBMC (peripheral blood mononuclear cells). PBMCrefer to blood cells having round lymphocytes and monocytes.Physiologically, PBMC are critical components of the mechanism againstinfection. PBMC may be isolated from heparinized whole blood of normalhealthy donors or huffy coats, by standard density gradientcentrifugation and harvested from the interface, washed (e.g.phosphate-buffered saline) and stored in freezing medium. PBMC may becultured in multi-well plates. At various times of culture, supernatantmay be either removed for assessment, or cells may be harvested andanalyzed (Smith R. et al (2003) Blood 102(7):2532-2540). The compoundsof this embodiment may further comprise a phosphonate or phosphonateprodrug. Typically, the phosphonate or phosphonate prodrug has thestructure A³ as described herein.

Optionally, the compounds of this embodiment demonstrate improvedintracellular half-life of the compounds or intracellular metabolites ofthe compounds in human PBMC when compared to analogs of the compoundsnot having the phosphonate or phosphonate prodrug. Typically, thehalf-life is improved by at least about 50%, more typically at least inthe range 50-100%, still more typically at least about 100%, moretypically yet greater than about 100%.

In another embodiment, the intracellular half-life of a metabolite ofthe compound in human PBMCs is improved when compared to an analog ofthe compound not having the phosphonate or phosphonate prodrug. In suchembodiments, the metabolite may be generated intracellularly, or it isgenerated within human PBMC. The metabolite may be a product of thecleavage of a phosphonate prodrug within human PBMCs. The phosphonateprodrug may be cleaved to form a metabolite having at least one negativecharge at physiological pH. The phosphonate prodrug may be enzymaticallycleaved within human PBMC to form a phosphonate having at least oneactive hydrogen atom of the form P—OH.

The compounds of the invention may have pre-organized binding modeswhich optimize the binding affinity of other, known HIV integraseinhibitors. During binding between the inhibitor and the active site ofthe target HIV integrase enzyme, the inhibitor may attain a low energyconformation (also called bound conformation) in order to interactwithin an active site. Generally, ligands of molecules with multiplerotational bonds exist in many potential conformational states, most ofwhich are not able to bind to the active site. The greater the number ofpossible ligand conformations typically results in a greater decrease inefficiency of the entropy contribution to the free energy of binding,and will result in less favorable binding affinities. One aspect ofdesigning pre-organized binding features in an integrase inhibitorcompound is incorporating conformational constraints that reduces thetotal number of conformational states and places the inhibitor into acorrect binding conformation (Lam, P. Y. S. et al. J. Med. Chem, (1996)39:3514-3525; Chen, J. M. et al. Biochemistry (1998) 37:17735-17744;Chen, J. M. et al. Jour. Amer. Chem. Soc. (2000) 122:9648-9654; Chen, J.M. et al U.S. Pat. No. 6,187,907; Chen, et al Bio. Org. Med. Chem.Letters (2002) 12:1195-1198). Knowledge of one or more preferred, i.e.low-energy, binding conformations is important for rational structuredesign and avoid inactive lead compounds.

Those of skill in the art will also recognize that the compounds of theinvention may exist in many different protonation states, depending on,among other things, the pH of their environment. While the structuralformulae provided herein depict the compounds in only one of severalpossible protonation states, it will be understood that these structuresare illustrative only, and that the invention is not limited to anyparticular protonation state—any and all protonated forms of thecompounds are intended to fall within the scope of the invention.

The compounds of this invention optionally comprise salts of thecompounds herein, especially pharmaceutically acceptable non-toxic saltscontaining, for example, Na⁺, Li⁺, K⁺, Ca⁺² and Mg⁺². Such salts mayinclude those derived by combination of appropriate cations such asalkali and alkaline earth metal ions or ammonium and quaternary aminoions with an acid anion moiety, typically a carboxylic acid. Thecompounds of the invention may bear multiple positive or negativecharges. The net charge of the compounds of the invention may be eitherpositive or negative. Any associated counter ions are typically dictatedby the synthesis and/or isolation methods by which the compounds areobtained. Typical counter ions include, but are not limited to ammonium,sodium, potassium, lithium, halides, acetate, trifluoroacetate, etc.,and mixtures thereof. It will be understood that the identity of anyassociated counter ion is not a critical feature of the invention, andthat the invention encompasses the compounds in association with anytype of counter ion. Moreover, as the compounds can exists in a varietyof different forms, the invention is intended to encompass not onlyforms of the compounds that are in association with counter ions (e.g.,dry salts), but also forms that are not in association with counter ions(e.g., aqueous or organic solutions).

Metal salts typically are prepared by reacting the metal hydroxide witha compound of this invention. Examples of metal salts which are preparedin this way are salts containing Li⁺, Na⁺, and K⁺. A less soluble metalsalt can be precipitated from the solution of a more soluble salt byaddition of the suitable metal compound. In addition, salts may beformed from acid addition of certain organic and inorganic acids, e.g.,HCl, HBr, H₂SO₄, H₃PO₄ or organic sulfonic acids, to basic centers,typically amines, or to acidic groups. Finally, it is to be understoodthat the compositions herein comprise compounds of the invention intheir unionized, as well as zwitterionic form, and combinations withstoichiometric amounts of water as in hydrates.

Also included within the scope of this invention are the salts of theparental compounds with one or more amino acids, especially thenaturally-occurring amino acids found as protein components. The aminoacid typically is one bearing a side chain with a basic or acidic group,e.g., lysine, arginine or glutamic acid, or a neutral group such asglycine, serine, threonine, alanine, isoleucine, or leucine.

The compounds of the invention can also exist as tautomeric, resonanceisomers in certain cases. Typically, the structures shown hereinexemplify only one tautomeric or resonance form of the compounds. Forexample, hydrazine, oxime, hydrazone groups may be shown in either thesyn or anti configurations. The corresponding alternative configurationis contemplated as well. All possible tautomeric and resonance forms arewithin the scope of the invention.

One enantiomer of a compound of the invention can be separatedsubstantially free of its opposing enantiomer by a method such asformation of diastereomers using optically active resolving agents(Stereochemisty of Carbon Compounds (1962) by E. L. Eliel, McGraw Hill;Lochmuller, C. H., (1975) J. Chromatogr., 113:(3) 283-302). Separationof diastereomers formed from the racemic mixture can be accomplished byany suitable method, including: (1) formation of ionic, diastereomericsalts with chiral compounds and separation by fractional crystallizationor other methods, (2) formation of diastereomeric compounds with chiralderivatizing reagents, separation of the diastereomers, and conversionto the pure enantiomers. Alternatively, enantiomers can be separateddirectly under chiral conditions, method (3).

Under method (1), diastereomeric salts can be formed by reaction ofenantiomerically pure chiral bases such as brucine, quinine, ephedrine,strychnine, α-methyl-β-phenethylamine(amphetamine), and the like withasymmetric compounds bearing acidic functionality, such as carboxylicacid and sulfonic acid. The diastereomeric salts may be induced toseparate by fractional crystallization or ionic chromatography. Forseparation of the optical isomers of amino compounds, addition of chiralcarboxylic or sulfonic acids, such as camphorsulfonic acid, tartaricacid, mandelic acid, or lactic acid can result in formation of thediastereomeric salts.

Alternatively, by method (2), the substrate to be resolved may bereacted with one enantiomer of a chiral compound to form adiastereomeric pair (Eliel, E. and Wilen, S. (1994) Stereochemistry ofOrganic Compounds, John Wiley & Sons, Inc., p. 322). Diastereomericcompounds can be formed by reacting asymmetric compounds withenantiomerically pure chiral derivatizing reagents, such as menthylderivatives, followed by separation of the diastereomers and hydrolysisto yield the free, enantiomerically enriched xanthene. A method ofdetermining optical purity involves making chiral esters, such as amenthyl ester or Mosher ester, α-methoxy-α-(trifluoromethyl)phenylacetate (Jacob III. (1982) J. Org. Chem. 47:4165), of the racemicmixture, and analyzing the NMR spectrum for the presence of the twoatropisomeric diastereomers. Stable diastereomers can be separated andisolated by normal- and reverse-phase chromatography following methodsfor separation of atropisomeric naphthyl-isoquinolines (Hoye, T., WO96/15111).

By method (3), a racemic mixture of two asymmetric enantiomers can beseparated by chromatography using a chiral stationary phase (ChiralLiquid Chromatography (1989) W. J. Lough, Ed. Chapman and Hall, NewYork; Okamoto, (1990) “Optical resolution of dihydropyridine enantiomersby High-performance liquid chromatography using phenylcarbamates ofpolysaccharides as a chiral stationary phase”, J. of Chromatogr.513:375-378).

Enantiomers can be distinguished by methods used to distinguish otherchiral molecules with asymmetric carbon atoms, such as optical rotationand circular dichroism.

Synthesis of HIV-Integrase Inhibitor Compounds

The compounds of the invention may be prepared by a variety of syntheticroutes and methods known to those skilled in the art. The invention alsorelates to methods of making the compounds of the invention. Thecompounds are prepared by any of the applicable techniques of organicsynthesis. Many such techniques are well known in the art. However, manyof the known techniques are elaborated in: “Compendium of OrganicSynthetic Methods”, John Wiley & Sons, New York, Vol. 1, Ian T. Harrisonand Shuyen Harrison, 1971; Vol. 2, Ian T. Harrison and Shuyen Harrison,1974; Vol. 3, Louis S. Hegedus and Leroy Wade, 1977; Vol. 4, Leroy G.Wade, jr., 1980; Vol. 5, Leroy G. Wade, Jr., 1984; and Vol. 6, MichaelB. Smith; as well as March, J., “Advanced Organic Chemistry”, ThirdEdition, John Wiley & Sons, New York, 1985; “Comprehensive OrganicSynthesis. Selectivity, Strategy & Efficiency in Modern OrganicChemistry” (9 Volume set) Barry M. Trost, Editor-in-Chief, PergamonPress, New York, 1993.

A number of exemplary methods for the preparation of the compounds,Formulas I-IV, of the invention are provided herein. These methods areintended to illustrate the nature of such preparations are not intendedto limit the scope of applicable methods.

Deliberate use may be made of protecting groups to mask reactivefunctionality and direct reactions regioselectively (Greene, et al(1991) “Protective Groups in Organic Synthesis”, 2nd Ed., John Wiley &Sons). For example, useful protecting groups for the 8-hydroxyl groupand other hydroxyl substituents include methyl, MOM (methoxymethyl),trialkylsilyl, benzyl, benzoyl, trityl, and tetrahydropyranyl. Certainaryl positions may be blocked from substitution, such as the 2-positionas fluorine.

Formula I Compounds

Exemplary methods of synthesis of Formula I compounds are describedbelow in Schemes 1-10 and 15-17. One method of synthesis of Formula Icompounds of the invention is cyclization of a succinimide compound witha pyridine dicarboxylate compound to give tricyclic compounds (Murrayand Semple, Synthesis (1996) 11:80-82; Jones and Jones, Jour. Chem.Soc., Perkin Transactions I (1973) 26-32), according to Scheme 1.

Alternatively, a succinimide with a labile protecting group (P) on thenitrogen may be reacted with a pyridine dicarboxylate compound. P may bean acid-labile protecting group, such as trialkylsilyl. Trialkylsilylgroups may also be removed with fluoride reagents. After P is removed, avariety of Ar-L groups may be covalently attached, according to Scheme2.

Imide compounds can be reduced with dissolving metal reducing agents,e.g. Zn, or hydride reagents, e.g. NaBH₄, to form a lactam. Exemplaryregioselective conversions shown in Scheme 3 include:

Imide compounds may also be reduced to the hydroxylactam under mildconditions. Reductions with sodium borohydride and cerium or samariumsalts have been shown to proceed with regioselectivity on asymmetricimides (Mase, et al J. Chem. Soc. Perkin Communication 1 (2002)707-709), as in Scheme 4, upper. Grignard reagents and acetylenic anions(Chihab-Eddine, et al Tetrahedron Lett. (2001) 42:573-576) may also addwith regioselectivity to an imide carbonyl to form alkyl-hydroxylactamcompounds, as in Scheme 4, lower). The phenolic oxygen groups may beprotected and deprotected as necessary to furnish yield reactions.

Another synthetic route to the compounds of the invention proceedsthrough substituted quinoline intermediates (Clemence, et al U.S. Pat.No. 5,324,839; Billhardt-Troughton, et al U.S. Pat. No. 5,602,146;Matsumura, J. Amer. Chem. Soc. (1935) 57:124-128) having the generalformula:

5,8-Dihydroxy quinoline compounds may be elaborated according to Scheme5:

The cyclic anhydride below may be regioselectively esterified to givethe compounds of the invention, for example via the route in Scheme 6where MOM is methoxymethyl and X is, for example, C(═O), CRC(═O),C(═O)C(═O), and SO₂. See Ornstein, et al Jour. Med. Chem. (1989)32:827-833. The same chemistry can be applied to the 5-membered lactamsynthesis to control the regiochemistry as in Scheme 7:

A cyclic imide may be conveniently alkylated, acylated, or otherwisereacted to form a broad array of compounds with Ar-L groups:

The Ar-L group may be attached as one reactant group, for example as analkylating reagent like benzyl bromide (Ar=phenyl, L=CH₂) or asulfonating reagent, like 4-methoxyphenyl sulfonyl chloride(Ar=4-methoxyphenyl, L=S(═O)₂. Alternatively, the Ar-L group may beattached by a multi step process. For example, the imide nitrogen mayreact with a sulfurizing reagent such as 2,2-dipyridyl disulfide to forman N-sulfide intermediate (Ar=2-pyridyl, L=S). Such an intermediate maybe further elaborated to a variety of Ar-L groups where L is S, S(═O) orS(═O)₂.

Another synthetic route to the compounds of the invention proceedsthrough 7-substituted, 8-quinolinol intermediates (Zhuang, et al WO02/36734; Vaillancourt, et al U.S. Pat. No. 6,310,211; Hodel, U.S. Pat.No. 3,113,135) having the general formulas, including aryl substitutedcompounds:

Annulation of the third, 5-7 membered ring can be conducted byappropriate selection of aryl substituents on the quinoline ring system,utilizing known synthetic transformations to give compounds of FormulaI. For example, methods for coupling carboxylic acids and otheractivated acyl groups with amines to form carboxamides are well known inthe art (March, J. Advanced Organic Chemistry, 3rd Edition, John Wiley &Sons, 1985, pp. 370-376). An exemplary cyclization includes thefollowing:

Scheme 8 below shows another synthetic route to compounds of theinvention, i.e. Formula 1. This route proceeds by cyclization of a2-O-protected, 3 halo-aniline compound with an (α,β-unsaturated carbonylcompound to give a functionalized quinoline. The α,β-unsaturatedcarbonyl compound may be, for example, an aldehyde (X═H), ketone (X═R),ester (X═OR), amide (X═NR2), acyl halide (X═Cl), or anhydride.Carbonylation via palladium catalysis can give an ester which may beelaborated to the amide functionality and cyclization to form a 5, 6, or7 membered ring. The R group of phenolic oxygen may be a labileprotecting group, e.g. trialkylsilyl or tetrahydropyranyl, which may beremoved at a step in the synthetic route, or it may be a substituentwhich is retained in the putative integrase inhibitor compound.

Halo quinoline intermediates may undergo a flexible array ofnucleophilic aromatic substitutions and Suzuki-type reactions, as shownin Scheme 9 below. Suzuki coupling of aryl halide compounds withacetylenic and vinylic palladium complexes are carbon-carbon bondforming reactions under relatively mild conditions. In some instances itmay be necessary to block the 2 position to direct reaction at thedesired aryl position.

Formula I compounds with a5,9-dihydroxy-pyrrolo[3,4-g]quinoline-6,8-dione were prepared byselective protection of the C9 phenol in5,9-dihydroxy-pyrrolo[3,4-g]quinolinie-6,8-dione. The C9 phenol wasprotected with a TIPS group and the C5 phenol could then be alkylated oracylated (Scheme 10)

Formula III Compounds

Formula III compounds may be prepared by the following methods inSchemes 11-14:

The acid 1 (WO02/30930, p. 173) may be reacted with amine 2 (preparedaccording to the methods described by T. Morie, et al, Chem. Pharm.Bull., 42, 1994, 877-882; D. Wenninger, et al, Nucleosides Nucleotides,16, 1997, 977-982) by the method of peptide coupling such as describedin WO02/30930, p. 173 to form amide 3. Bromination with NBS generatescompound 4. The phenol is protected with a bulky acyl group such aspivaloyl. Displacement of bromine at C5 of naphthyridine by Bis-bocprotected hydrazine is achieved using the method reported by J. B.Arteburn, et al, Org. Lett., 3, 2001, 1351-1354. The silyl protectinggroup is removed by TBAF (T. Green and P. Wuts, “Protective Groups inOrganic Synthesis”, p. 142, Wiley Science, 1999) and mesylate 7 isformed by reacting the alcohol formed with methanesulfonyl chloride.Treatment of compound 7 with TFA followed by heating hydrazino mesylatein the basic condition affords hydrazono triaza anthracene 8.

Compound 8 is converted to many different derivatives, e.g. carbazones 9(R¹═COR³) are generated by reaction with acid chlorides or activatedcarboxylic acids. Carbamates 9 (R¹═COOR³) are obtained upon reaction of8 with chloro formates ClCOOR³. Semicarbazones 9 (R¹═CONR²R³) are formedusing isocyanates or N,N-dialkyl chloroformaides. Thiosemicarbazones 9(R¹═CSNR³R⁴) are generated with thioisocyanates. Sulfonyl ureas 9(R¹═SO₂NR³R⁴) are obtained by reaction of 8 with sulfamoyl chloridesusing procedures reported by M. L. Matier, et al, J. Med. Chem., 15,1972, 538-541. The simple sulfonamides are produced when 8 reacts withsulfonyl chlorides. The ester group in compounds 9 is removed uponsaponification to give compound 10.

Alternatively, many of hydrazone derivatives 9 are subjected toalkylation followed by saponification to afford compounds 11.

Compound 5 from Scheme 11 is reacted with a substituted hydroxyamine oramine (R⁵=Boc; R⁶═OR^(a) or alkyl) in a manner similar to that describedby L. A., Carpino et al, Org. Lett., 3, 2001, 2793-2795 to givederivative 12. After transforming the silyl protected hydroxyl in 12 toa leaving group such as the mesylate in 13, cyclization is accomplishedin the heating condition and the presence of a base to afford compound14. Final deprotection by hydrolysis of 14 gives compound 15.

When R⁶ in 14 is OR^(a), or where R^(a) can be removed, oxime 16 isobtained and can be functionalized with many reagents to yield compound17. Hydrolysis of ester group affords 18. For example, when 16 istreated with an alkyl halide (R⁷—X) or an alcohol under Mitsunobucondition, an ether 18 is formed. When an isocyanate or thioisocyanateis applied, a carbamate or thiocarbamate 18 (R⁷: C(═O)NHR⁸ or C(═S)NHR⁸)is generated. An N,N-disubstituted carbamate 18 (R⁷: C(═O)NR²R³) isobtained when a chloroformate ClC(═O)NR²R³ is reacted with 16.Similarly, treating 16 with a sulfamoyl chlorides affords a sulfamate 18(R⁷: SO₂NR¹R²).

Scheme 15 depicts one of the methods to prepare aspiro-cyclopropane-containing lactam fused to quinoline, an embodimentof Formula I. A differentially protected phenol 19 is used where R⁸ canbe a removable ether group such as trimethylsilyethyl ether and R⁹ canbe a bulky group such as diphenylmethyl or t-butyl ether. The carbonylof C6 is converted to an olefin regioselectively by treating 19 withmethylmagnesium bromide followed by dehydration of aminal to give 20.Carbene insertion by Simmons-Smith reaction (for examples Y. Biggs etal, JOC, 57, 1992, 5568-5573) produces cyclopropane 21. Selectiveremoval of R⁸ by TBAF followed by fuctionalization using the methodsdescribed in many examples leads to compound 24.

A dimethyl substituted lactam can be prepared by reacting 19 with aGrignard reagent followed by converting aminal 25 to acetate 26 andtreating 26 with Me₃Al/TMSOTf, a method reported by C. U. Kim, et al,Tetrahedron Letters, 35, 1994, 3017-3020, to afford 27. An alternativemethod can be used by reducing cyclopropane 21 with PtO₂/H₂ as reportedby C. K. Cheung et al, JOC, 54, 1989, 570-573, to give 27.

Another version of modified lactam can be obtained according to Scheme17. Treating 19 with an allyl Grignard reagent gives 30. Activatingaminal 30 by forming acetate 31 followed by treating 31 with allyltrimethylsilane mediated by a Lewis acid such as TMSOTf affords 32.Cyclization can be achieved by using Grubb's RCM (ring closuremetathesis) method (P. Schwab et al, Angew. Chem. Intl. 34, 1995, 2039).Alternatively, the terminal olefins in 32 can be converted to aldehydesand reductive amination leads to a spiro-piperidine.

Many tricyclic compounds can bear a heterocycle different from9-hydroxy-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one, i.e. Formula IV.Some examples and methods to prepare Formula IV compounds are depictedin Schemes 18-24 above.

Preparation of the Intermediate Phosphonate Esters Iaa-IVcc.

The structures of the intermediate phosphonate esters Iaa to IVcc areshown in Chart 1, in which the substituents R¹, R², R³, R⁴, A¹ and A²are as previously defined. The groups A^(1a) and A^(2a) are the same asthe groups A¹ and A², except that a substituent link—P(O)(OR⁵)₂ isappended. The substituent R⁵ is hydrogen, alkyl, alkenyl, aralkyl, oraryl. Subsequent chemical modifications to the compounds Iaa to Vcc, asdescribed herein, permit the synthesis of the final compounds of thisinvention.

The intermediate compounds Iaa to IVcc incorporate a phosphonate moiety(R⁵O)₂P(O) connected to the nucleus by means of a variable linkinggroup, designated as “link” in the attached structures. Chart 2illustrates examples of the linking groups present in the structuresIaa-IVcc.

Schemes A1-A33 illustrate the syntheses of the intermediate phosphonatecompounds of this invention, Iaa-IVcc, and of the intermediate compoundsnecessary for their synthesis.

The methods described for the introduction of phosphonate substituentsare, with modifications made by one skilled in the art, transferablewithin the substrates I-V. For example, reaction sequences which producethe phosphonates Iaa are, with appropriate modifications, applicable tothe preparation of the phosphonates IIaa, IIIaa, or IVaa. Methodsdescribed below for the attachment of phosphonate groups to reactivesubstituents such as OH, NH₂, CH₂Br, COOH, CHO etc are applicable toeach of the scaffolds I-V.

Scheme A34 illustrates methods for the interconversion of phosphonatediesters, monoesters and acids.

Protection of Reactive Substituents.

Depending on the reaction conditions employed, it may be necessary toprotect certain reactive substituents from unwanted reactions byprotection before the sequence described, and to deprotect thesubstituents afterwards, according to the knowledge of one skilled inthe art. Protection and deprotection of functional groups are described,for example, in Protective Groups in Organic Synthesis, by T. W. Greeneand P. G. M Wuts, Wiley, Second Edition 1990. Reactive substituentswhich may be protected are shown in the accompanying schemes as, forexample, [OH], [SH], etc.

Preparation of the Intermediate Phosphonate Esters 1aa.

Schemes A1-A5 illustrate methods for the preparation of the intermediatephosphonate esters Iaa.

As shown in Scheme A1, the phenolic hydroxyl substituent present in thetricyclic compound A1.1 is protected to afford the derivative A1.2. Theprotection of hydroxyl groups is described in Protective Groups inOrganic Synthesis, by T. W. Greene and P. G. M Wuts, Wiley, SecondEdition 1990, p. 10. For example, hydroxyl substituents are protected astrialkylsilyloxy, methoxymethyl, benzyl or tert-butyl ethers.Trialkylsilyl groups are introduced by the reaction of the phenol with achlorotrialkylsilane and a base such as imidazole, for example asdescribed in Protective Groups in Organic Synthesis, by T. W. Greene andP. G. M Wuts, Wiley, Second Edition 1990, p. 10ff. The protected productA1.2 is then reacted, in the presence of a strong base, with abromoalkyl phosphonate A1.3, to give the alkylation product A1.4. Thereaction is effected in a polar organic solvent such asdimethylformamide, dimethylacetamide, diglyme, tetrahydrofuran and thelike, in the presence of a base such as sodium hydride, an alkali metalalkoxide, lithium hexamethyldisilazide, and the like, at from ambienttemperature to about 100° C., to yield the alkylated product A1.4. Thephenolic hydroxyl group is then deprotected to afford the phenol A1.5.Methods for the deprotection of hydroxyl groups are described inProtective Groups in Organic Synthesis, by T. W. Greene and P. G. MWuts, Wiley, Second Edition 1990, p. 10ff.

For example,7-(4-fluoro-benzyl)-9-hydroxy-5H-1,7-diaza-anthracene-6,8-dione A1.6 isreacted with one molar equivalent of chlorotriisopropylsilane andimidazole in dimethylformamide at ambient temperature, as described inTet. Lett., 2865, 1974, to produce7-(4-fluoro-benzyl)-9-triisopropylsilanyloxy-5H-1,7-diaza-anthracene-6,8-dioneA1.7. The product is then reacted in dimethylformamide solution at about60° C. with one molar equivalent of a dialkyl 2-bromoethyl phosphonateA1.8 (Aldrich) and lithium hexamethyldisilazide, to yield the alkylatedproduct A1.9. The silyl protecting group is then removed by reactionwith tetrabutylammonium fluoride in tetrahydrofuran, as described in J.Org. Chem., 51, 4941, 1986, to give the phenolic product A1.10.

Using the above procedures, but employing, in place of the4-fluorobenzyl-substituted phenol A1.6, different phenols A1.1 and/ordifferent phosphonates A1.3, the corresponding products A1.5 areobtained.

Scheme A2 illustrates the preparation of phosphonate esters of structureIaa in which the phosphonate group is attached by means of an aryl ofheteroaryl ring.

In this procedure, a hydroxy-substituted phthalimide derivative A2. 1(Formula I) is protected, as described above, to afford the productA2.2. This compound is then reacted with a bromoaryl magnesium bromideGrignard reagent A2.3, in which the group Ar¹ is an aromatic orheteroaromatic group such as, for example, benzene or thiophene, toafford the carbinol A2.4. The regioselective addition of organometallicderivatives to phthalimides is described in Scheme 4. The reaction isperformed between approximately equimolar amounts of the reactants in anethereal solvent such as diethyl ether, tetrahydrofuran and the like, atfrom −40° C. to ambient temperature, to give the carbinol product A2.4.This material is then reacted with a dialkyl phosphite A2.5 and apalladium catalyst, to give the phosphonate A2.6. The preparation ofarylphosphonates by means of a coupling reaction between aryl bromidesand dialkyl phosphites is described in J. Med. Chem., 35, 1371, 1992.The reaction is conducted in a hydrocarbon solvent such as benzene,toluene or xylene, at about 100° C., in the presence of a palladium (0)catalyst such as tetrakis(triphenylphosphine)palladium(0), and atertiary base such as triethylamine or diisopropylethylamine. Thehydroxyl group is then deprotected to yield the phenolic product A2.7.Optionally, the benzylic hydroxyl substituent in the product A2.7 isremoved by means of a reductive procedure, as shown on Scheme 4.Benzylic hydroxyl groups are removed by catalytic hydrogenation, forexample by the use of 10% palladium on carbon in the presence ofhydrogen or a hydrogen donor, or by means of chemical reduction, forexample employing triethylsilane and boron trifluoride etherate.

For example,7-(3,5-dichloro-benzyl)-5,9-bis-triisopropylsilanyloxy-pyrrolo[3,4-g]quinoline-6,8-dioneA2.9, prepared by silylation of the corresponding diol, which is reactedwith one molar equivalent of 4-bromophenyl magnesium bromide A2.10 inether at 0° C. to produce the carbinol A2.11. The latter compound isthen reacted, in toluene solution at reflux, with a dialkyl phosphiteA2.5, triethylamine and tetrakis(triphenylphosphine)palladium(0), asdescribed in J. Med. Chem., 35, 1371, 1992, to afford the phosphonateproduct A2.12. Desilylation, for example by reaction with tetrabutylammonium fluoride, gives the diol product A2.13. Optionally, the productA2.12 is reduced, for example by reaction in dichloromethane solution atambient temperature with ca. four molar equivalents of triethylsilaneand boron trifluoride etherate, as described in Example 18 to yieldafter deprotection the reduced product A2.14.

Using the above procedures, but employing, in place of the3,5-dichlorobenzyl-substituted phenol derivative A2.9, different phenolderivatives A2.1 and/or different bromoaryl Grignard reagents A2.3, thecorresponding products A2.7 and A2.8 are obtained.

Scheme A3 illustrates the preparation of phosphonate esters of structureIaa in which the phosphonate group is attached by means of an alkylenechain.

In this sequence, a 6-aminoquinoline ester A3.1, prepared, for example,from the corresponding carboxylic acid by means of a Curtiusrearrangement, (Advanced Organic Chemistry, Part B, by F. A. Carey andR. J. Sundberg, Plenum, 2001, p.646) is reacted, under reductiveamination conditions, with a dialkyl formylalkyl phosphonate A3.2. Thepreparation of amines by means of reductive amination procedures isdescribed, for example, in Comprehensive Organic Transformations, by R.C. Larock, VCH, p 421, and in Advanced Organic Chemistry, Part B, by F.A. Carey and R. J. Sundberg, Plenum, 2001, p 269. In this procedure, theamine component and the aldehyde or ketone component are reactedtogether in the presence of a reducing agent such as, for example,borane, sodium cyanoborohydride, sodium triacetoxyborohydride ordiisobutylaluminum hydride, optionally in the presence of a Lewis acid,such as titanium tetraisopropoxide, as described in J. Org. Chem., 55,2552, 1990. The product A3.3 is then converted, by reaction with theamine ArBNH₂ A3.4, or a derivative thereof, into the amide A3.5. Theconversion of esters into amides is described in Comprehensive OrganicTransformations, by R. C. Larock, VCH, 1989, p. 987. The reactants arecombined in the presence of a base such as sodium methoxide underazeotropic conditions, or of a dialkyl aluminum or trialkyl tinderivative of the amine. The use of trimethylaluminum in the conversionof esters to amides is described in J. Med. Chem. Chim. Ther., 34, 1999,1995, and Syn. Comm., 25, 1401, 1995. The reaction is conducted in aninert solvent such as dichloromethane or toluene. The amide product A3.5is then cyclized by reaction with a reagent such as phosgene or afunctional equivalent thereof, such as triphosgene or a dialkylcarbonate, or a reagent such as diiodomethane, to give the cyclizedproduct A3.6 in which D is CO or CH₂. The reaction is conducted in anaprotic solvent such as tetrahydrofuran, in the presence of an inorganicor organic base such as potassium carbonate or diisopropylethylamine.

For example, the amine A3.7, prepared by means of a Curtiusrearrangement of the corresponding MOM-protected carboxylic acid, isreacted in isopropanol solution with a dialkyl formylmethyl phosphonateA3.8, prepared as described in Zh. Obschei. Khim., 1987, 57, 2793,sodium cyanoborohydride and acetic acid, to give the reductive aminationproduct A3.9. The product is then reacted with an excess of3,4-dichlorobenzylamine and sodium methoxide in toluene at reflux, toyield the amide A3.10. The latter compound is then reacted with onemolar equivalent of triphosgene and N,N-dimethylaminopyridine indichloromethane, to afford the cyclized product A3.11. The MOMprotecting groups are then removed, for example by reaction with acatalytic amount of methanolic hydrogen chloride, as described in J.Chem. Soc., Chem. Comm., 298, 1974, to give the dihydroxy product A3.12.

Using the above procedures, but employing, in place of the amine A3.7,different amines A3.1, and/or different aldehydes A3.2, and/or differentamines A3.4, the corresponding products A3.6 are obtained.

Scheme A4 illustrates the preparation of phosphonate esters of structureIaa in which the phosphonate group is attached by means of an alkylenechain or an aryl, heteroaryl or aralkyl group and a heteroatom O, S orN. In this sequence, a tricyclic aminal A4.1 is reacted in the presenceof an acid catalyst with a hydroxy, mercapto or amino-substituteddialkyl phosphonate A4.2 in which X is O, S, NH or N-alkyl, and R isalkyl, alkenyl, aryl, heteroaryl or aralkyl. The reaction is effected atambient temperature in an inert solvent such as dichloromethane, in thepresence of an acid such as p-toluenesulfonic acid or trifluoroaceticacid and an excess of the reagent A4.2. The hydroxyl group is thendeprotected to yield the phenolic product A4.4.

For example,7-(4-fluoro-benzyl)-6-hydroxy-5-methoxy-9-triisopropylsilanyloxy-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-oneA4.5 (Example 20, Scheme 15) is reacted at ambient temperature indichloromethane solution with a dialkyl 2-mercaptoethyl phosphonate A4.6(Zh. Obschei. Khim., 1973, 43, 2364) and trifluoroacetic acid to givethe thioether product A4.7, which upon deprotection withtetrabutylammonium fluoride yields the phenol A4.8.

As a further example,6-hydroxy-5-methoxy-7-(4-trifluoromethyl-benzyl)-9-triisopropylsilanyloxy-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-oneA4.9, prepared analogously to the 4-fluoro analog A4.5, is reacted,under the same conditions, with a dialkyl 3-mercaptophenyl phosphonateA4.10 to give the thioether A4.11 which upon deprotection affords thephenol A4.12. The phosphonate reagent A4.10 is obtained by palladium (0)catalyzed coupling reaction, as described in Scheme A2, between adialkyl phosphite and an S-protected derivative of 3-bromothiophenol,for example the S-trityl derivative, followed by removal of the sulfurprotecting group. Protection and deprotection of thiols is described inProtective Groups in Organic Synthesis, by T. W. Greene and P. G. MWuts, Wiley, Second Edition 1990, p. 277.

Using the above procedures, but employing, in place of the carbinolsA4.5 and A4.9, different carbinols A4.1, and/or different alcohols,thiols or amines A4.2, the corresponding products A4.4 are obtained.

Scheme A5 illustrates the preparation of phosphonate esters of structureIaa in which the phosphonate group is attached to a 7-membered ring bymeans of an alkylene or arylmethylene chain. In this sequence, asuitable protected quinoline acid ester A5.1 is subjected to a Curtiusrearrangement, as described in Scheme A3 to yield the amine A5.2. Theproduct is then reductively aminated, as described in Scheme A3, with aphosphonate aldehyde A5.3, in which the group R is an alkyl group or anaryl group, to give the amine product A5.4. This material is thencoupled with the glycine derivative A5.5 to yield the amide A5.6. Thepreparation of amides from carboxylic acids and derivatives isdescribed, for example, in Organic Functional Group Preparations, by S.R. Sandler and W. Karo, Academic Press, 1968, p. 274, and ComprehensiveOrganic Transformations, by R. C. Larock, VCH, 1989, p. 972ff. Thecarboxylic acid is reacted with the amine in the presence of anactivating agent, such as, for example, dicyclohexylcarbodiimide ordiisopropylcarbodiimide, optionally in the presence of, for example,hydroxybenztriazole, N-hydroxysuccinimide or N-hydroxypyridone, in anon-protic solvent such as, for example, pyridine, DMF ordichloromethane, to afford the amide. Alternatively, the carboxylic acidmay first be converted into an activated derivative such as the acidchloride, anhydride, mixed anhydride, imidazolide and the like, and thenreacted with the amine, in the presence of an organic base such as, forexample, pyridine, to afford the amide. The conversion of a carboxylicacid into the corresponding acid chloride can be effected by treatmentof the carboxylic acid with a reagent such as, for example, thionylchloride or oxalyl chloride in an inert organic solvent such asdichloromethane, optionally in the presence of a catalytic amount ofdimethylformamide. The product A5.6 is then cyclized, for example byheating at reflux temperature in toluene in the presence of a basiccatalyst such as sodium methoxide, or by reaction withtrimethylaluminum, as described in Syn. Comm., 25, 1401, 1995, to affordafter deprotection of the hydroxyl groups, the diazepindione derivativeA5.7.

For example, the MOM-protected amine A3.7 is reductively aminated byreaction with a dialkyl phosphonoacet aldehyde A5.8 (Aurora) and sodiumtriacetoxyborohydride, to produce the amine A5.9. The product is thencoupled in dimethylformamide solution, in the presence of dicyclohexylcarbodiimide, with (4-fluoro-benzylamino)-acetic acid A5.10, to give theamide A5.11. This material is converted, by reaction withtrimethylaluminum in dichloromethane, as described above, into thediazepin derivative A5.12. Removal of the MOM protecting groups, aspreviously described, then affords the phenolic product A5.13.

Using the above procedures, but employing, in place of the amine A3.7,different amines A5.2, and/or different aldehydes A5.3, and/or differentcarboxylic acids A5.5, the corresponding products A5.7 are obtained.

Preparation of the Intermediate Phosphonate Esters Ibb.

Schemes A6-A16 illustrate methods for the preparation of the phosphonateesters of general structure Ibb.

Scheme A6 depicts two methods for the preparation of phosphonate estersin which the phosphonate group is linked by means of a saturated orunsaturated alkylene chain, or alkylene chains incorporatingcarbocyclic, aryl or heteroaryl rings. In this procedure, amono-protected phenol A6.1, for example, is reacted either with abromo-substituted alkyl phosphonate A6.2, in which the group R isalkylene, cycloalkyl, alkenyl, aralkyl, heterarylalkyl and the like, orwith an analogous hydroxyl-substituted dialkyl phosphonate A6.3. Thereaction between the phenol and the bromo compound A6.2 is conducted ina polar organic solvent such as dimethylformamide, in the presence of abase such as potassium carbonate, and optionally in the presence of acatalytic amount of potassium iodide, to afford the ether product A6.4.Alternatively, the ether compounds A6.4 are obtained by means of aMitsunobu reaction between the phenol A6.1 and the hydroxy compoundA6.3. The preparation of aromatic ethers by means of the Mitsunobureaction is described, for example, in Comprehensive OrganicTransformations, by R. C. Larock, VCH, 1989, p. 448, and in AdvancedOrganic Chemistry, Part B, by F. A. Carey and R. J. Sundberg, Plenum,2001, p. 153-4 and in Org. React., 1992, 42, 335, The phenol and thealcohol component are reacted together in an aprotic solvent such as,for example, tetrahydrofuran, in the presence of a dialkylazodicarboxylate and a triarylphosphine, to afford the ether orthioether products. The procedure is also described in Org. React.,1992, 42, 335-656. Deprotection of the phenolic hydroxyl group thenaffords the phenol A6.5.

For example,7-(4-fluoro-benzyl)-5-hydroxy-9-triethylsilanyloxy-pyrrolo[3,4-g]quinoline-6,8-dioneA6.6, (Example 12, Scheme 11) is reacted at ambient temperature indimethoxyethane solution with one molar equivalent of a dialkyl4-bromo-2-butenylphosphonate A6.7 (J. Med. Chem., 1992, 35, 1371) andpotassium carbonate, to yield the ether product A6.8, which upondeprotection with tetrabutylammonium fluoride gives the phenol A6.9.

As a further example,7-[2-(4-fluoro-phenyl)-ethyl]-5-hydroxy-9-triethylsilanyloxy-pyrrolo[3,4-g]quinoline-6,8-dioneA6.10 prepared by analogous procedures to those shown is reacted intetrahydrofuran solution with a dialkyl 3-hydroxypropyl phosphonateA6.11 (Acros), diethyl azodicarboxylate and triphenylphosphine, toafford the ether product A6.12 which upon deprotection gives the phenolA6.13.

Using the above procedures, but employing, in place of the phenols A6.6and A6.10, the phenols A6.1, and/or different bromides A6.2, or alcoholsA6.3, the corresponding products A6.5 are obtained.

Scheme A7 illustrates the preparation of phosphonate esters of structureIbb in which the phosphonate is linked by means of an aryl or aheteroaryl group.

In this procedure, a mono-protected phenol A7.1 (Formula I) is convertedinto the triflate A7.2 by reaction, in an inert solvent such asdichloromethane, with trifluoromethanesulfonyl chloride or anhydride, orwith trimethylsilyl triflate and triethylsilane, in each case in thepresence of a tertiary base such as triethylamine. The triflate is thencoupled with a bromo-substituted arylboronate A7.3, in which the groupAr¹ is an aromatic or heteroaromatic moiety, to afford the coupledproduct A7.4. The Suzuki coupling of aryl triflates and aryl boronicacids is described in Palladium Reagents and Catalysts by J. Tsuji,Wiley 1995, p 218. The reactants are combined in an inert solvent suchas toluene or dioxan, in the presence of a palladium (0) catalyst suchas tetrakis(triphenylphosphine)palladium and a base such as sodiumbicarbonate. The coupled product A7.4 is then reacted, as describedpreviously (Scheme A2) with a dialkyl phosphate A7.5, to give thephosphonate ester A7.6, which upon deprotection yields the phenol A7.7.

For example, trifluoro-methanesulfonic acid9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-5-ylester A7.8 (Example 46) is reacted in dioxan solution at 70° C. with onemolar equivalent of 3-bromophenyl boronic acid A7.9 (Maybridge), sodiumbicarbonate and a catalytic amount of tri-(o-tolyl)phosphine, to producethe coupled compound A7.10. This material is then reacted, as describedin Scheme A2, with a dialkyl phosphite and a palladium (0) catalyst, togive the phosphonate product A7.10. Removal of the benzhydryl protectinggroup, for example by treatment with trifluoroacetic acid and anisole indichloromethane, as described in Tet. Lett., 25, 3909, 1984, thenaffords the phenol A7.11.

Using the above procedures, but employing, in place of the phenol A7.8,the phenol A7.1, and/or different boronic acids A7.3, the correspondingproducts A7.7 are obtained.

Scheme A8 illustrates the preparation of phosphonate esters of structureIbb in which the phosphonate group is linked by means of a oxygen,sulfur or nitrogen and an aliphatic or aromatic moiety.

In this method, a monoprotected phenol A8.1 (Formula I) is convertedinto the corresponding triflate A8.2, as described above (Scheme A7).The product is then subjected to a nucleophilic displacement reactionwith various carbinols, thiols or amines A8.3, in which the group R isan acyclic or cyclic saturated or unsaturated alkylene, or aryl, aralkylor heteroaryl moiety, to afford after deprotection the ether, thioetheror amine products A8.4. The displacement reaction is performed in aninert solvent such as dichloroethane or dioxan, at from ambienttemperature to about 80° C., in the presence of a tertiary organic basesuch as N-methyl morpholine and the like.

For example, trifluoro-methanesulfonic acid9-benzhydryloxy-7-(4-fluoro-benzyl)-6,8-dioxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-5-ylester A8.5 (Example 56) is reacted in dioxan at 50° C. with one molarequivalent of a dialkyl methylaminomethyl phosphonate A8.6 anddiisopropylethylamine, to give the amine product A8.7. Deprotection thenaffords the phenol A8.8.

Using the above procedures, but employing, in place of the triflateA8.5, different triflates A8.2, and/or different carbinols, thiols oramines A8.3, the corresponding products A8.4 are obtained.

Scheme A9 depicts the preparation of phosphonate esters of structure Ibbin which the phosphonate group is attached by means of a methylaminogroup and a carbon link R, in which the group R is an acyclic or cyclicsaturated or unsaturated alkylene, or aryl, aralkyl or heteroarylmoiety. The compounds are obtained by means of a reductive alkylationreaction, as described above (Scheme A3) between the aldehyde A9.1,prepared by the method shown in Example 49, and a dialkyl aminoalkyl oraryl phosphonate A9.2. The amination product A9.3 is then deprotected togive the phenol A9.3.

For example,9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-5-carbaldehydeA9.5 (Example 49) is reacted with a dialkyl aminopropyl phosphonate A9.6(Acros), sodium cyanoborohydride and acetic acid in isopropanol to yieldthe amination product A9.7, which is deprotected to produce the phenolA9.8.

Using the above procedures, but employing, in place of the aldehydeA9.5, different aldehydes A9.1, and/or different amines A9.2, thecorresponding products A9.4 are obtained.

Scheme A10 depicts the preparation of phosphonate esters of structureIbb in which the phosphonate group is attached by means of an amidelinkage and a carbon link R, in which the group R is an acyclic orcyclic saturated or unsaturated alkylene, or aryl, aralkyl or heteroarylmoiety. In this sequence, the aldehyde A10.1, prepared, for example, asshown in Example 49 is oxidized to the corresponding carboxylic acidA10.2. The conversion of an aldehyde to the corresponding carboxylicacid is described in Comprehensive Organic Transformations, by R. C.Larock, VCH, 1989, p. 838. The reaction is effected by the use ofvarious oxidizing agents such as, for example, potassium permanganate,ruthenium tetroxide, silver oxide or sodium chlorite. The carboxylicacid is then coupled, as described in Scheme A5, with an amine A10.3 toafford the amide, which upon deprotection gives the phenolic amideA10.4.

For example,9-benzhydryloxy-7-(4-chloro-benzyl)-6,8-dioxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-5-carbaldehydeA10.5, prepared using the methods described in Example 49, is treatedwith silver oxide in acetonitrile, as described in Tet. Lett., 5685,1968, to produce the corresponding carboxylic acid9-benzhydryloxy-7-(4-chloro-benzyl)-6,8-dioxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-5-carboxylicacid A10.6. This material is then coupled, in dimethylformamidesolution, with one molar equivalent of a dialkyl aminoethyl phosphonateA10.7 (Aurora) and dicyclohexyl carbodiimide, to afford the amide, whichupon deprotection gives the phenolic product A10.8.

Using the above procedures, but employing, in place of the aldehydeA10.5, different aldehydes A10.1, and/or different amines A10.3, thecorresponding products A10.4 are obtained.

Scheme A11 depicts the preparation of phosphonate esters of structureIbb in which the phosphonate group is attached by means of a methylenegroup. In this procedure, a hydroxymethyl-substituted O-protected phenolA11.1, prepared by the method shown in Example 50, is converted into thecorresponding bromomethyl derivative A11.2. The conversion of alcoholsinto the corresponding bromides is described, for example, inComprehensive Organic Transformations, by R. C. Larock, VCH, 1989, p.356ff. For example, benzyl alcohols can be transformed into the bromocompounds by reaction with bromine and triphenyl phosphite, or byreaction with trimethylsilyl chloride and lithium bromide, or withcarbon tetrabromide and triphenylphosphine, as described in J. Am. Chem.Soc., 92, 2139, 1970. The resultant bromomethyl compound A11.2 istreated with a trialkyl phosphite A11.3 in an Arbuzov reaction. Thepreparation of phosphonates by means of the Arbuzov reaction isdescribed in Handb. Organophosphorus Chem., 1992, 115-72. The bromocompound is heated with an excess of the phosphite at from about 80°C.-130° C. to produce the phosphonate product, which upon deprotectionaffords the phenolic phosphonate A11.4.

For example,9-benzhydryloxy-5-hydroxymethyl-7-(4-methoxy-benzyl)-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-oneA11.5 prepared by the method shown in Example 50, is reacted indichloromethane with one molar equivalent of carbon tetrabromide andtriphenylphosphine to produce9-benzhydryloxy-5-bromomethyl-7-(4-methoxy-benzyl)-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-oneA11.6. The product is then heated at 120° C. with an excess of atrialkyl phosphite A11.3. The resulting phosphonate is then deprotectedto afford the phenolic product A11.7.

Using the above procedures, but employing, in place of the carbinolA11.5, different carbinols A11.1, and/or different phosphites A11.3, thecorresponding products A11.4 are obtained.

Scheme A12 depicts the preparation of phosphonate esters of structureIbb in which the phosphonate group is attached by means of amethyleneoxy and a variable alkyl moiety. In this procedure, a protectedhydroxymethyl-substituted tricyclic phenol A12.1 prepared according tothe procedure of Example 50, is alkylated with a dialkylbromo-substituted phosphonate A12.2, in which the group R is an acyclicor cyclic saturated or unsaturated alkylene, or aryl, aralkyl orheteroaryl moiety. The carbinol is reacted with one molar equivalent ofthe bromo compound in a polar aprotic organic solvent such asdimethylacetamide, dioxan and the like, in the presence of a strong basesuch as sodium hydride, lithium hexamethyldisilazide, or potassium tert.butoxide. The thus-obtained ether A12.3 is then deprotected to give thephenol A12.4.

For example,9-benzhydryloxy-7-(4-fluoro-benzyl)-5-hydroxymethyl-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-oneA12.5 (Example 50) is treated in dimethylformamide solution at ambienttemperature with one molar equivalent of lithium hexamethyldisilazide,followed by one molar equivalent of a dialkyl 4-(bromomethyl)benzylphosphonate A12.6 (Tet., 1998, 54, 9341) to yield the alkylated productA12.7. Deprotection then gives the phenol A12.8.

Using the above procedures, but employing, in place of the carbinolA12.5, different carbinols A12.1, and/or different bromo compoundsA12.2, the corresponding products A12.4 are obtained.

Scheme A13 depicts the preparation of phosphonate esters of structureIbb in which the phosphonate group is attached by means of an aryl orheteroaryl ethenyl or ethyl linkage. In this procedure, avinyl-substituted OH-protected phenol A13.1, prepared by the methodshown in Example 59, is coupled in a palladium-catalyzed Heck reactionwith a dibromo-substituted aromatic or heteroaromatic reagent A13.2, inwhich the group Ar¹ is an aromatic or heteroaromatic ring. The couplingof aryl halides with olefins by means of the Heck reaction is described,for example, in Advanced Organic Chemistry, by F. A. Carey and R. J.Sundberg, Plenum, 2001, p. 503ff and in Acc. Chem. Res., 12, 146, 1979.The aryl bromide and the olefin are coupled in a polar solvent such asdimethylformamide or dioxan, in the presence of a palladium(0) catalystsuch as tetrakis(triphenylphosphine)palladium(0) or a palladium(II)catalyst such as palladium(II) acetate, and optionally in the presenceof a base such as triethylamine or potassium carbonate. The coupledproduct A13.3 is then reacted, as described in Scheme A7, with a dialkylphosphite A13.4 and a palladium catalyst, to afford, after deprotectionof the phenolic hydroxyl, the ethenyl phosphonate ester A13.5. Catalyticor chemical reduction of the product then yields the saturated analogA13.6. The reduction reaction is effected chemically, for example by theuse of diimide or diborane, as described in Comprehensive OrganicTransformations, by R. C. Larock, VCH, 1989, p. 5, or catalytically, forexample by the use of a palladium on carbon catalyst in the presence ofhydrogen or a hydrogen donor.

For example,9-benzhydryloxy-7-(4-fluoro-benzyl)-5-vinyl-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-oneA13.7 (Example 59) is reacted in dimethylformamide with2,5-dibromothiophene A13.8 and a catalytic amount of palladium (II)acetate and triethylamine, to give the coupled product A13.9. Thismaterial is then coupled with a dialkyl phosphite, as described above,to afford after deprotection of the phenol, the ethenylthienylphosphonate A13.10. The latter compound is reacted with diimide,prepared by basic hydrolysis of diethyl azodicarboxylate, as describedin Angew. Chem. Int. Ed., 4, 271, 1965, to yield the saturated productA13.11.

Using the above procedures, but employing, in place of thevinyl-substituted compound A13.7, different analogs A13.1, and/ordifferent dibromo compounds A13.2, the corresponding products A13.5 areobtained.

Scheme A14 depicts the preparation of phosphonate esters of structureIbb in which the phosphonate group is attached by means of an alkoxychain incorporating an amide linkage. In this procedure, amono-protected phenol A14.1 (Example 6) is alkylated with a methylbromoalkyl carboxylate A14.2. The alkylation reaction is conducted undersimilar conditions to those described in Scheme A6, to afford the esterether A14.3. Hydrolysis of the ester group then gives the carboxylicacid A14.4. Hydrolysis methods for converting esters into carboxylicacids are described, for example, in Comprehensive OrganicTransformations, by R. C. Larock, VCH, 1989, p 981. The methods includethe use of enzymes such as pig liver esterase, and chemical methods suchas the use of alkali metal hydroxides in aqueous organic solventmixtures, for example lithium hydroxide in an aqueous organic solvent.

The resultant carboxylic acid is then coupled, as described in SchemeA10, with a dialkyl amino-substituted phosphonate A14.5, in which thegroup R is an acyclic or cyclic saturated or unsaturated alkylene, oraryl, aralkyl or heteroaryl moiety, to produce the amide A14.6.Deprotection then yields the phenol A14.7.

For example,5-hydroxy-9-methoxymethoxy-7-(4-methyl-benzyl)-pyrrolo[3,4-g]quinoline-6,8-dioneA14.8, prepared, for example, by the method shown in Example 6 isreacted in dimethylformamide solution with methyl bromoacetate A14.9 andcesium carbonate, to give the ether A14.10. The ester group is thenhydrolyzed by reaction with one molar equivalent of lithium hydroxide inaqueous glyme, to produce the carboxylic acid A14.11. The carboxylicacid is then coupled in dimethylformamide solution in the presence ofdiisopropyl carbodiimide with a dialkyl 2-aminoethyl phosphonate A14.12,(J. Org. Chem., 2000, 65, 676) to form the amide A14.13. Deprotection,for example by the use of 50% aqueous acetic acid containing a catalyticamount of sulfuric acid, as described in J. Am. Chem. Soc., 55, 3040,1933, then affords the phenol A14.14.

Using the above procedures, but employing, in place of the phenol A14.8,different phenols A14.1, and/or different bromoesters A14.2, and/ordifferent amines A14.5, the corresponding products A14.7 are obtained.

Scheme A15 depicts the preparation of phosphonate esters of structureIbb in which the phosphonate group is attached by means of an alkylenechain incorporating an amide linkage. In this procedure, the malonicester derivative of a protected phenol A15.1, prepared, for example, bythe methods shown in Example 86, is hydrolyzed and decarboxylated togive the corresponding acetic acid derivative A15.2. Hydrolysis anddecarboxylation of malonic esters is described, for example, in AdvancedOrganic Chemistry, Part B, by F. A. Carey and R. J. Sundberg, Plenum,2001, p. 15. The ester hydrolysis is effected under conventional basicconditions, and decarboxylation occurs after acidification eitherspontaneously or under mild heating. The resultant acetic acidderivative is then coupled, as described previously, with a dialkylamino-substituted phosphonate A15.3, to give the amide product whichupon deprotection affords the phenol A15.4.

For example,2-[9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-5-yl]-malonicacid dimethyl ester A15.5 (Example 86) is reacted at ambient temperaturewith two molar equivalents of lithium hydroxide in aqueousdimethoxyethane, and the reaction mixture is then acidified to pH 4.0and heated at reflux to effect decarboxylation and production of theacetic acid derivative A15.6. The carboxylic acid is then coupled inacetonitrile solution in the presence of a water-soluble carbodiimidewith a dialkyl 4-aminophenyl phosphonate A15.7 (Epsilon) to yield afterdeprotection the phenolic amide A15.8.

Using the above procedures, but employing, in place of the malonic esterA15.5, different malonic esters A15.1, and/or different amines A15.3,the corresponding products A15.4 are obtained.

Scheme A16 depicts the preparation of phosphonate esters of structureIbb in which the phosphonate group is attached by means of an alkoxychain and the nucleus incorporates a benzazepin moiety. In thisprocedure, a quinoline monoester A16.1 is decarboxylated to afford theester A16.2. Decarboxylation of carboxylic acids is described inAdvanced Organic Chemistry, Part B, by F. A. Carey and R. J. Sundberg,Plenum, 2001, p. 676 and in Advanced Organic Chemistry, By J. Marsh,McGraw Hill, 1968, p. 435. The carboxylic acid is decarboxylatedthermally in the presence of copper powder and quinoline, or byconversion to an ester with N-hydroxyphthalimide orN-hydroxythiopyridine, followed by photolysis in the presence of ahydrogen donor. The decarboxylated product A16.2 is then converted intothe allyl ether A16.3 by reaction with allyl bromide in a polar solventsuch as dimethylformamide in the presence of a base such h astriethylamine or potassium carbonate. The allyl ester is then subjectedto a thermal Claisen rearrangement to afford the allyl-substitutedphenol A16.4. The Claisen rearrangement of allyl aryl ethers isdescribed in Advanced Organic Chemistry, By J. Marsh, McGraw Hill, 1968,p. 830 and in Advanced Organic Chemistry, Part B, by F. A. Carey and R.J. Sundberg, Plenum, 2001, p. 394. The reaction is conducted in ahigh-boiling solvent or without solvent at ca. 200° C. The free phenolichydroxyl group is then protected to yield the doubly protected productA16.5. The latter compound is then subjected to a hydroborationprocedure to afford the carbinol A16.6. Hydroboration of alkenes isdescribed, for example, in Advanced Organic Chemistry, Part B, by F. A.Carey and R. J. Sundberg, Plenum, 2001, p. 226. The olefin is reactedwith diborane or a substituted borane such as 9-BBN or catechyl borane,and the resulting borane is oxidized, for example with hydrogenperoxide, oxygen, sodium peroxycarbonate or a tertiary amine oxide. Theresultant carbinol A16.6 is then converted into the substituted amineA16.7. The conversion is effected in two stages. In the first step, thecarbinol is converted into a leaving group such as mesylate, tosylate orbromide by reaction with, for example, methanesulfonyl chloride,p-toluenesulfonyl chloride or triphenylphosphine/carbon tetrabromide. Inthe second step, the activated intermediate is reacted in a polarsolvent such as N-methylpyrrolidinone or acetonitrile with the amineArBNH₂ to give the product A16.7. The aminoester is then cyclized toyield the azepin derivative A16.8. The cyclization reaction is performedunder similar conditions to those described above (Scheme A5). Forexample, the aminoester is heated in xylene at reflux temperature in thepresence of a catalytic amount of sodium isopropoxide. The doublyprotected azepin derivative A16.8 is then selectively deprotected togive the phenol A16.9. The procedure for the selective deprotection isdependent on the nature of the protecting groups. For example, if thephenol A16.1 is protected as the benzhydryl derivative, the phenol A16.4is protected as, for example, the TIPS derivative. Deprotection of theazepin A16.8 is then effected by treatment with tetrabutylammoniumfluoride in tetrahydrofuran. The phenol A16.9 is then reacted with adialkyl hydroxy-substituted phosphonate A16.10, in which the group R isan alkylene or alkenyl chain, optionally incorporating an aryl orheteroaryl group. The reaction is performed under the conditions of theMitsunobu reaction, as described in Scheme A6. The resultant ether isthen deprotected to afford the phenol A16.11.

For example, 8-benzhydryloxy-7-methyl-quinolin-5-ol A16.12 prepared asdescribed above from the corresponding carboxyester is converted, viaallylation, rearrangement and hydroboration/oxidation, as describedabove, into3-(8-benzhydryloxy-7-methyl-5-triisopropylsilanyloxy-quinolin-6-yl)-propan-1-olA16.13. The latter compound is then converted into an activatedderivative which is reacted, as described above, with3-chloro-4-fluorobenzylamine A16.14 to yield[3-(8-benzhydryloxy-7-methyl-5-triisopropylsilanyloxy-quinolin-6-yl)-propyl]-(3-chloro-4-fluoro-benzyl)-amineA16.15. Cyclization of the product, for example by reaction withtrimethylaluminum, employing the conditions described above affords11-benzhydryloxy-9-(3-chloro-4-fluoro-benzyl)-5-triisopropylsilanyloxy-6,7,8,9-tetrahydro-1,9-diaza-cyclohepta[b]naphthalen-10-oneA16.16. The compound is deprotected by reaction with tetrabutylammoniumfluoride, to produce11-benzhydryloxy-9-(3-chloro-4-fluoro-benzyl)-5-hydroxy-6,7,8,9-tetrahydro-1,9-diaza-cyclohepta[b]naphthalen-10-oneA16.17. The product is then reacted with a dialkyl hydroxyethylphosphonate A16.18, diethyl azodicarboxylate and triphenylphosphine intetrahydrofuran to give after deprotection the phenolic ether A16.19.

Using the above procedures, but employing, in place of the phenolA16.12, different phenols A16.2, and/or different hydroxyesters A16.10,and/or different amines ArBNH₂, the corresponding products A16.11 areobtained.

Preparation of the Intermediate Phosphonate Esters Icc.

Scheme A17 illustrates methods for the preparation of phosphonate estersof structure Icc in which the phosphonate group is attached by means ofa one-carbon link, or by saturated or unsaturated multicarbon chainsoptionally incorporating a heteroatom. In this procedure, a4-methyl-substituted quinoline A17.3 is prepared by means of aDoebner-von Miller condensation between an enone A17.2 and a substitutedaniline A17.1. The preparation of quinolines by means of the Doebner-vonMiller reaction is described in Heterocyclic Chemistry, by T. L.Gilchrist, Longman, 1992, p. 158. The reaction is performed by heatingequimolar amounts of the reactants in an inert solvent such asdimethylacetamide. The bromohydroxyquinoline A17.3 is then transformed,by means of reaction sequence such as that illustrated in Scheme 8 intothe protected tricyclic compound A17.4. Benzylic bromination of thelatter compound, for example by reaction with N-bromosuccinimide orN-bromoacetamide in an inert solvent such as ethyl acetate at ca. 60°C., then yields the bromomethyl derivative A17.5. This compound is thenreacted in an Arbuzov reaction, as described above (Scheme A11), with atrialkyl phosphite to produce after deprotection the phosphonate esterA17.8.

Alternatively, the bromomethyl derivative A17.5 is reacted, using theconditions described in Scheme A12, with a dialkyl hydroxy, mercapto oramino-substituted phosphonate A17.6, in which the group R is an acyclicor cyclic saturated or unsaturated alkylene, or aryl, aralkyl orheteroaryl moiety, to give after deprotection the ether, thioether oramino product A17.7.

Alternatively, the methyl-substituted tricyclic compound A17.4 iscondensed, under basic conditions, with a dialkyl formyl-substitutedphosphonate A17.9. The reaction is conducted between equimolar amountsof the reactants in a polar solvent such as dioxan or dimethylformamide,in the presence of a strong base such as sodium hydride or lithiumtetramethyl piperidide. The procedure affords after deprotection theunsaturated phenol A17.10. Reduction of the double bond, as describedabove (Scheme A13) then produces the saturated analog A17.11.

For example, benzoic acid7-cyclopent-3-enylmethyl-4-methyl-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-9-ylester A17.12 is reacted with N-bromosuccinimide in refluxing ethylacetate to afford benzoic acid4-bromomethyl-7-cyclopent-3-enylmethyl-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-9-ylester A17.13. This compound is heated to 120° C. with an excess of atrialkyl phosphite to give after deprotection the phenolic phosphonateester A17.14.

As a further example,4-bromomethyl-7-(4-fluoro-benzyl)-9-triisopropylsilanyloxy-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-oneA17.15, prepared by bromination of the corresponding methyl compound isreacted with a dialkyl 2-mercaptoethyl phosphonate A17.16 (Zh. Obschei.Khim., 1973, 43, 2793) and cesium carbonate in acetonitrile, to give thethioether product A17.17. Deprotection yields the corresponding phenolA17.18.

As a further example,7-(3-chloro-4-fluoro-benzyl)-9-methoxymethoxy-4-methyl-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-oneA17.19 is condensed in dioxan solution with a dialkyl formylmethylphosphonate A17.20 (Aurora) in the presence of lithiumtetramethylpiperidide to form the unsaturated product A17.21.Deprotection then yields the phenol A17.22; reduction of the double bondthen gives the saturated analog A17.23.

Using the above procedures, but employing, in place of the startingmaterials A17.12, A17.15 and A17.19, different starting materials A17.4or A17.5, and/or different carbinols, thiols or amines A17.6 oraldehydes A17.9, the corresponding products A17.7, A17.8, A17.10 andA17.11 are obtained.

Preparation of the Intermediate Phosphonate Esters IIaa.

Schemes A18 and A19 illustrate the preparation of phosphonate esters ofstructure IIaa. Scheme A18 depicts the preparation of phosphonate estersof structure IIaa in which the phosphonate group is attached by means ofan alkoxy, alkylthio or alkylamino group. In this procedure, analkoxyethene triester A18.1 (JP 61289089) and a 3-aminopyridine A18.2are reacted together, as described in JP 61289089 and GB 1509695, toproduce the pyridylamino triester A18.3. The reaction is performed usingequimolar amounts of the reactants at a temperature of about 150° C. Theproduct is then cyclized to afford the 1,5-naphthyridine derivativeA18.4. The reaction is performed in a high-boiling solvent such asdiphenyl ether at a temperature of about 250° C. The diester is thenconverted to the anhydride, and the later compound is transformed byreaction with the amine ArBNH₂, and protection of the phenolic hydroxylgroup, into the cyclic imide A18.5. This material is then reduced, asdescribed in Example 20, for example by the use of sodium borohydride,to afford the hydroxylactam A18.6. The latter compound is then reacted,in the presence of an acid catalyst, as described in Scheme A4, with adialkyl hydroxy, mercapto or amino-substituted phosphonate A18.7, inwhich the group R is an acyclic or cyclic saturated or unsaturatedalkylene, or aryl, aralkyl or heteroaryl moiety, to yield afterdeprotection of the phenolic hydroxy group, the ether, thioether oramino product A18.8.

For example, the triester A18.1 is reacted with 3-aminopyridine A18.9 toafford the pyridylamino triester A18.10. The product is heated indiphenyl ether at 250° C. to form the 1,5-naphthyridine A18.11. Thelatter compound is then transformed, as described above, into7-(4-fluoro-benzyl)-6-hydroxy-9-triisopropylsilanyloxy-6,7-dihydro-pyrrolo[3,4-b][1,5]naphthyridin-8-oneA18.12. The hydroxylactam is then reacted in dichloromethane solutionwith a dialkyl 4-hydroxybutyl phosphonate A18.13 (J. Med. Chem., 1996,39, 949) and trifluoroacetic acid, by a similar reaction as Example 23,to generate the phosphonate product A18.14.

Using the above procedures, but employing, in place of the pyridineA18.9, different pyridines A18.2, and/or different phosphonates A18.7,the corresponding products A18.8 are obtained.

Scheme A19 depicts the preparation of phosphonate esters of structureIIaa in which the phosphonate group is attached by means of variablecarbon linkage, and the nucleus is a 1,3,5,9-tetraazaanthracene. In thisprocedure, the 1,5-naphthyridine A18.4 is converted into thephenol-protected analog A19.1. The product is then subjected to aselective partial hydrolysis, for example by reaction with one molarequivalent of a base such as lithium hydroxide in an aqueous organicsolvent mixture, to produce the carboxy ester A19.2. The product is thensubjected to a Curtius rearrangement, as described in Scheme A3, toafford the amine A19.3. The product is then reductively aminated, asdescribed in Scheme A3, by reaction with a dialkyl formyl-substitutedphosphonate A19.4, in which the group R is an acyclic or cyclicsaturated or unsaturated alkylene, or aryl, aralkyl or heteroarylmoiety, to give the amine A19.5. The ester group is then transformed, asdescribed previously (Scheme A3), into the amide A19.6, by reaction withthe amine ArBNH₂. The product is then cyclized to afford, afterdeprotection of the phenolic hydroxyl, the tricyclic product, A19.7, inwhich A is, for example, CO or CH₂, by reaction respectively withphosgene or an equivalent thereof, or with diiodomethane or a similarreagent.

For example, 2-amino-4-hydroxy-[1,5]naphthyridine-3-carboxylic acidmethyl ester A19.8, prepared as described in Scheme A18 by the reactionbetween 3-aminopyridine and 1,2,2-tris-(carbomethoxy)-1-ethoxyethene, isconverted, as described above, into2-amino-4-benzyloxy-[1,5]naphthyridine-3-carboxylic acid methyl esterA19.9. The amine is then reacted in isopropanol solution with a dialkyl3-formylphenyl phosphonate A19.10 ( J. Med. Chem., 1984, 27, 654) andsodium triacetoxyborohydride, to yield the amine A19.11. The ester groupof the latter compound is then transformed into the amide by reactionwith 3,5-dichlorophenethylamine-trimethyl aluminum, as describedpreviously, to afford the amide A19.12. The product is then reacted withtriphosgene in pyridine solution at 80° C. to give the cyclized productA19.13. Deprotection then yields the phenol A19.14.

Using the above procedures, but employing, in place of the amine A19.9,different amines A19.3, and/or different formyl phosphonates A19.4, thecorresponding products A19.7 are obtained.

Preparation of the Intermediate Phosphonate Esters IIcc.

Scheme A20 illustrates the preparation of phosphonate esters ofstructure IIcc, in which the phosphonate group is attached by means of aone-carbon or multicarbon link, or by means of a heteroatom and avariable carbon linkage. In this procedure, the triester A18.1 isreacted, as described in Scheme A18, with a 3-amino-4-methylpyridineA20.1 to give the substituted pyridine product A20.2. The lattercompound is then transformed, as described previously, into themethyl-substituted tricyclic compound A20.3. This compound is thensubjected to benzylic bromination, for example by reaction withN-bromosuccinimide, to form the bromomethyl product A20.4. This compoundis subjected to an Arbuzov reaction with a trialkyl phosphite, asdescribed in Scheme A11, to afford after deprotection the phosphonateA20.5.

Alternatively, the bromomethyl compound A20.4 is reacted with a dialkylphosphonate A20.6 in which X is O, S, NH or N-alkyl, and R is an acyclicor cyclic saturated or unsaturated alkylene, or aryl, aralkyl orheteroaryl moiety, using the procedures described in Scheme A17, togive, after deprotection of the phenolic hydroxyl, the ether, thioetheror amine products A20.7.

Alternatively, the methyl compound A20.3 is subjected, as described inScheme A17, to a base-catalyzed condensation reaction with a dialkylformyl-substituted phosphonate A20.8, in which R is an acyclic or cyclicsaturated or unsaturated alkylene, or aryl, aralkyl or heteroarylmoiety, to generate after deprotection of the phenolic hydroxyl, theunsaturated product A20.9. The double bond is then reduced, as describedin Scheme A17, to afford the saturated analog A20.10.

For example, condensation between the triester A18.1 and3-amino-4-methylpyridine A20.11 gives the pyridine product A20.12. Thecompound is then transformed, as described above, into7-[1-(4-fluoro-phenyl)-1-methyl-ethyl]-4-methyl-9-triisopropylsilanyloxy-pyrrolo[3,4-b][1,5]naphthyridine-6,8-dioneA20.13. The latter compound is then reacted with a dialkyl formylethylphosphonate A20.14 (Zh. Obschei. Mum., 1987, 57, 2793) and lithiumtetramethylpiperidide in tetrahydrofuran to afford after deprotectionthe unsaturated product A20.15. The product is then reduced withdiimide, as described above, (Scheme A13) to yield the saturated analogA20.16.

As a further example,7-[1-(4-fluoro-phenyl)-cyclopropyl]-4-methyl-9-triisopropylsilanyloxy-pyrrolo[3,4-b][1,5]naphthyridine-6,8-dioneA20.17, prepared according to the procedures described above, is reactedwith N-bromosuccinimide in refluxing ethyl acetate to give4-bromomethyl-7-[1-(4-fluoro-phenyl)-cyclopropyl]-9-triisopropylsilanyloxy-pyrrolo[3,4-b[1,5]naphthyridine-6,8-dioneA20.18. The product is then heated at 120° C. with excess of a trialkylphosphite to give after deprotection the phosphonate A20.19.

As a further example,4-bromomethyl-7-(3-chloro-4-fluoro-benzyl)-9-triisopropylsilanyloxy-pyrrolo[3,4-b][1,5]naphthyridine-6,8-dioneA20.20, prepared according to the procedures described above, is reactedin dimethylformamide solution with a dialkyl methylaminomethylphosphonate A20.21(AsInEx) and potassium carbonate, to afford afterdeprotection the displacement product A20.22.

Using the above procedures, but employing, in place of the startingmaterials A20.13, A20.17 and A20.20, different starting materials A20.3or A20.4, and/or different carbinols, thiols or amines A20.6 oraldehydes A20.8, the corresponding products A20.5, A20.7, A20.9 andA20.10 are obtained.

Preparation of the Intermediate Phosphonate Esters IIIaa.

Scheme A21 illustrates methods for the preparation of phosphonates ofstructure IIIaa in which the phosphonate group is attached by means of aheteroatom and a variable carbon link. In this sequence, acarbomethoxymethyl derivative of the amine ArBNH₂, A21.1 is coupled withthe 1,6-naphthyridine carboxylic acid A21.2, prepared as described in WO0230930, using the methods described previously, to prepare the amideA21.3. Bromination, for example using N-bromosuccinimide, yields the5-bromo derivative A21.4. Protection of the phenolic hydroxyl group,followed by displacement of the bromine with a hydrazine orhydroxylamine nucleophile, as described for example in Example 69,affords the 5-imino derivative A21.5 in which X is NH₂ or OH. Lactamformation, for example by the use of potassium tert. butoxide inrefluxing xylene, or by the use of trimethylaluminum, then gives thetricyclic product A21.6, which upon protection of the X substituentgives the product A21.7. Reduction of this material, for example bytreatment with sodium borohydride, for example as in Example 20, thengives the aminol A21.8. The latter compound is reacted with a dialkylhydroxy, mercapto, or amino-substituted phosphonate A21.9, in which thegroup R is an acyclic or cyclic saturated or unsaturated alkylene, oraryl, aralkyl or heteroaryl moiety, in the presence of an acid such astrifluoroacetic acid, as described in Scheme A4, to yield the ether,thioether or amine product A21.10. Deprotection then gives the phenolA21.11.

For example, (4-fluoro-benzylamino)-acetic acid methyl ester A21.12 iscoupled in tetrahydrofuran solution with one molar equivalent of8-hydroxy-[1,6]naphthyridine-7-carboxylic acid A21.13, (WO 0230930) inthe presence of diisopropyl carbodiimide, to form[(4-fluoro-benzyl)-(8-hydroxy-[1,6]naphthyridine-7-carbonyl)-amino]-aceticacid methyl ester A21.14. The latter compound is then transformed, bybromination, displacement and cyclization, as described above into thetricyclic product,9-benzyloxy-7-(4-fluoro-benzyl)-10-hydrazono-6,7-dihydro-10H-1,7,10a-triaza-anthracene-5,8-dioneA21.15. The hydrazono compound is then converted into the N,N-dibenzylderivative A21.16. The conversion of amines into dibenzylamines, forexample by treatment with benzyl bromide in a polar solvent such asacetonitrile or aqueous ethanol, in the presence of a base such astriethylamine or sodium carbonate, is described in Protective Groups inOrganic Synthesis, by T. W. Greene and P. G. M Wuts, Wiley, SecondEdition 1990, p. 364. The tribenzylated compound is then reduced with alimited amount of sodium borohydride in isopropanol to afford the aminalA21.17. This compound is reacted with a dialkyl 2-mercaptoethylphosphonate A21.18 (Zh. Obschei. Khim., 1973, 43, 2364), andtrifluoroacetic acid in dichloromethane, to give the thioether A21.19.Debenzylation, for example by the use of 5% palladium on carbon in thepresence of ammonium formate, as described in Tet. Lett, 28, 515, 1987,then affords the hydrazono phenol A21.20.

Using the above procedures, but employing, in place of the amide A21.14,different amides A21.3, and/or different phosphonates A21.9, thecorresponding products A21.11 are obtained.

Preparation of the Intermediate Phosphonate Esters IIIbb.

Schemes A22-A24 illustrate methods for the preparation of phosphonateesters of structure IIIbb.

Scheme A22 illustrates methods for the preparation of phosphonates ofstructure IIIbb in which the phosphonate group is attached by means of avariable carbon linkage. In this sequence, the naphthyridine carboxylicacid A21.2 is coupled, as described previously, with the aminederivative A22.1, following a procedure similar to Example 28, to formthe amide A22.2. Bromination, as described above, yields the 5-bromoderivative A22.3, which upon protection of the phenolic hydroxyl yieldsthe compound A22.4. Displacement of the bromine, by reaction with adialkyl amino-substituted phosphonate A22.5, in which the group R is anacyclic or cyclic saturated or unsaturated alkylene, or aryl, aralkyl orheteroaryl moiety, affords the amine A22.6. The reaction is performed ina polar organic solvent such as dimethylformamide in the presence of abase such as potassium carbonate. Deprotection of the alcoholic hydroxylgroup affords the carbinol A22.7, which upon activation and cyclization,for example as described in Scheme 11 then gives the tricyclic productA22.8, which upon deprotection affords the phenol A22.9.

For example, acetic acid5-bromo-7-[(4-fluoro-benzyl)-propyl-carbamoyl]-[1,6]naphthyridin-8-ylester A22.10, is reacted with one molar equivalent of a dialkylaminopropyl phosphonate A22.11, (Acros) to yield the amine A22.12.Deprotection and activation of the alcoholic hydroxyl group, for exampleby conversion to the mesylate, followed by cyclization under basicconditions, and deprotection of the phenolic hydroxyl group, thenaffords the enol A22.13.

Using the above procedures, but employing, in place of the bromideA22.10, different bromides A22.4, and/or different aminophosphonatesA22.5, the corresponding products A22.9 are obtained.

Scheme A23 illustrates methods for the preparation of phosphonates ofstructure IIIbb in which the phosphonate group is attached by means of anitrogen and a variable carbon linkage. In this sequence, a tricyclicimine A23.1 (Scheme 12) is reacted with a dialkyl bromoalkyl phosphonateA23.2 to give the alkylated product A23.3. The reaction is performed ina polar organic solvent such as acetonitrile or dimethylsulfoxide, inthe presence of a base such as diisopropylethylamine or 2,6-lutidine.

Alternatively, the imine A23.1 is converted into a hydrazone A23.5 byreaction with a dialkyl formyl-substituted phosphonate A23.4 in whichthe group R is an acyclic or cyclic saturated or unsaturated alkylene,or aryl, aralkyl or heteroaryl moiety. The hydrazone is prepared by thereaction of equimolar amounts of the reactants in a polar organicsolvent such as ethanol, optionally in the presence of a catalyticamount of an acid such as acetic acid. Optionally, the hydrazone productA23.5 is reduced, for example by treatment with sodium borohydride, togive the dihydro derivative A23.6.

For example, acetic acid7-(4-fluoro-benzyl)-10-hydrazono-8-oxo-6,7,8,10-tetrahydro-5H-1,7,10a-triaza-anthracen-9-ylester A23.7 (Scheme 12) is reacted at 60° C. in dimethylformamidesolution containing potassium carbonate with one molar equivalent of adialkyl 2-bromoethyl phosphonate A23.8 (Aldrich), to prepare thealkylated product which upon deprotection yields the enol A23.9.

As a further example, the hydrazone A23.7 is reacted in ethanol solutionat ambient temperature with one molar equivalent of a dialkyl2-formylphenyl phosphonate A23.10 (Epsilon) to give the hydrazoneproduct A23.11. Reduction of the double bond, by treatment with sodiumcyanoborohydride in isopropanol, followed by deprotection, affords theenol product A23.12.

Using the above procedures, but employing, in place of the hydrazoneA23.7, different hydrazones A23.1, and/or different bromophosphonatesA23.2, or formyl phosphonates A23.4 the corresponding products A23.3,A23.5 and A23.6 are obtained.

Scheme A24 illustrates methods for the preparation of phosphonates ofstructure IIIbb in which the phosphonate group is attached by means of ahydroxyimino linkage. In this sequence, a tricyclic oxime A24.1 (Scheme14) is reacted with a dialkyl bromo-substituted phosphonate A24.2 inwhich the group R is an acyclic or cyclic saturated or unsaturatedalkylene, or aryl, aralkyl or heteroaryl moiety. The reaction isperformed in a polar organic solvent in the presence of a base such assodium hydride or lithium hexamethyldisilazide. Deprotection then yieldsthe enol A24.4.

For example, acetic acid7-(4-fluoro-benzyl)-10-hydroxyimino-8-oxo-6,7,8,10-tetrahydro-5H-1,7,10a-triaza-anthracen-9-ylester A24.5 (Scheme 14) is reacted in dimethylformamide solution withone molar equivalent of sodium hydride, followed by the addition of onemolar equivalent of a dialkyl 4-(bromomethyl)phenyl phosphonate A24.6(Tet., 1998, 54, 9341) to afford after deprotection the iminoetherA24.7.

Using the above procedures, but employing, in place of the oxime A24.5,different oximes A24.1, and/or different phosphonates A24.2, thecorresponding products A24.4 are obtained.

Preparation of the Intermediate Phosphonate Esters IIIcc.

Scheme A25 illustrates methods for the preparation of phosphonates ofstructure IIIcc. The conversion of pyridine-2,3-dicarboxylic anhydride(A25.1, R═H) into the naphthyridine A25.2, R═H, is described in WO0255079. Using the same procedure, 4-methylpyridine-2,3-dicarboxylicanhydride A25.1, R=Me, (J. Org. Chem., 1961, 26, 808) is converted intothe naphthyridine A25.2, R=Me. This compound is then transformed, asdescribed in Scheme 12, into the imine A25.3. Protection of the hydroxyland amino groups then furnishes the derivative A25.4. The product isthen condensed under basic conditions, as described in Scheme A20, witha dialkyl formyl-substituted phosphonate A25.5, in which the group R isan acyclic or cyclic saturated or unsaturated alkylene, or aryl, aralkylor heteroaryl moiety. After deprotection, the product A25.6 isoptionally reduced, as described in Scheme A20, to give the saturatedanalog A25.17.

Alternatively, the methyl-substituted tricycle A25.4 is brominated, forexample by reaction with N-bromosuccinimide, to give the bromomethylproduct A25.7. The compound is then subjected to a Arbuzov reaction witha trialkyl phosphite, to yield after deprotection the phosphonate A25.8.

Alternatively, the bromomethyl compound A25.7 is reacted, as describedpreviously (Scheme A20) with a dialkyl hydroxy, mercapto oramino-substituted phosphonate A25.18, in which the group R is an acyclicor cyclic saturated or unsaturated alkylene, or aryl, aralkyl orheteroaryl moiety, to give after deprotection the ether, thioether oramine product A25.9.

For example, acetic acid7-[2-(4-fluoro-phenyl)-ethyl]-10-hydrazono-4-methyl-8-oxo-6,7,8,10-tetrahydro-5H-1,7,10a-triaza-anthracen-9-ylester A25.10, prepared according to the procedures described above, isconverted into the phthalimido derivative by reaction with one molarequivalent of phthalic anhydride, as described in J. Org. Chem., 43,2320, 1978. The protected product is then reacted withN-bromosuccinimide in hexachloroethane to give the bromomethylderivative A25.12. This compound is heated to 120° C. with an excess ofa trialkyl phosphite to produce the phosphonate A25.13. Deprotection,for example by reaction with ethanolic hydrazine, as described in J.Org. Chem., 43, 2320, 1978, then affords the phosphonate A25.14.

As a further example, the phthalimido-protected methyl-substitutedtricycle A25.11 is reacted in dioxan solution with a dialkylformylphosphonate A25.12 (Tet., 1994, 50, 10277) and lithium tetramethylpiperidide, to yield, after removal of the protecting groups, theunsaturated phosphonate A25.13. Reduction of the double bond then givesthe saturated analog A25.14.

As a further example, the bromomethyl derivative A25.12 is reacted inacetonitrile solution with one molar equivalent of a dialkyl2-mercaptopropyl phosphonate A25.15 (WO 007101) anddiisopropylethylamine, to produce after deprotection the phosphonateA25.16.

Using the above procedures, but employing, in place of the startingmaterials A25.10, A25.11 or A25.12, different starting materials A25.4and A25.7, and/or different aldehydes A25.5 or alcohols, thiols oramines A25.18, the corresponding products A25.6, A25.8, A25.9 and A25.17are obtained.

Preparation of the Intermediate Phosphonate Esters IVaa.

Schemes A29 and A30 illustrates the preparation of phosphonate esters ofstructure IVaa.

Scheme A29 illustrates the preparation of compounds in which phosphonateis attached by means of an ether, tioether of amine linkage. In thisprocedure, a substituted succinimide A29.1 is condensed, as described inScheme 1 and Example 2, with a heterocyclic diester A29.2 to affordafter protection the tricyclic product A29.3. Reduction with sodiumborohydride then yields the aminal A29.4, which upon acid-catalyzedreaction with a dialkyl hydroxy, mercapto or amino-substitutedphosphonate A29.S, in which the group R is an acyclic or cyclicsaturated or unsaturated alkylene, or aryl, aralkyl or heteroarylmoiety, to give after deprotection the ether, thioether or amineproducts A29.6.

For example, 1-[2-(4-fluoro-phenyl)-cyclopropyl]-pyrrolidine-2,5-dioneA29.7, prepared from 4-fluorophenylcyclopropylamine (J. Med. Chem.,1996, 39, 1485) and succinic anhydride, is reacted with4,5-dicarbomethoxyisoxazole A29.8 (Chem Ber., 97, 1414, 1964) to affordafter protection6-[2-(4-fluoro-phenyl)-cyclopropyl]-4,8-bis-methoxymethoxy-oxazolo[4,5-f]isoindole-5,7-dioneA29.9. Reduction with sodium borohydride then gives the aminal A29.10,which upon reaction with a dialkyl 3-mercaptopropyl phosphonate A29.11(WO 0077101) and trifluoroacetic acid in dichloromethane yields thephosphonate thioether A29.12.

Using the above procedures, but employing, in place of the startingmaterials A29.7 and A29.8, different starting materials A29.1 and A29.2,and/or different phosphonates A29.5, the corresponding products A29.6are obtained.

Preparation of the Intermediate Phosphonate Esters IVaa.

Scheme A30 illustrates the preparation of phosphonate esters ofstructure IVaa in which the phosphonate is attached by means of avariable carbon linkage. In this procedure, dimethyl succinate A30.1 iscondensed, under base catalysis, for example using the proceduredescribed on Scheme 1 and Example 2 with a heterocyclic diester A30.2,to yield after protection of the phenolic hydroxyl groups, the diesterA30.3. Partial basic hydrolysis, for example by reaction with one molarequivalent of lithium hydroxide in aqueous dimethoxyethane, then affordsthe monoacid A30.4. The carboxylic acid is homologated to produce thecorresponding acetic acid A30.5. The transformation is effected by meansof the Arndt Eistert reaction. In this procedure, which is described inAdvanced Organic Chemistry, Part B, by F. A. Carey and R. J. Sundberg,Plenum, 2001, p. 641, and in Advanced Organic Chemistry, By J. Marsh,McGraw Hill, 1968, p. 809, the carboxylic acid is converted into theacid chloride, which is reacted with diazomethane to give thecorresponding diazoketone. Silver-catalyzed Wolff rearrangement of thediazoketone in an alcoholic solvent then yields the acetic acid ester,which upon hydrolysis yields the acetic acid A30.5. This material iscoupled with the amine A30.6 to give the amide A30.7. Base-catalyzedthermal cyclization of the latter compound, for example by refluxing inxylene with sodium methoxide, then gives the cyclized product A30.8. Thelatter compound is then alkylated, as described above, (Scheme A10) witha dialkyl bromo-substituted phosphonate A30.9, in which the group R isan acyclic or cyclic saturated or unsaturated alkylene, or aryl, aralkylor heteroaryl moiety, to afford after deprotection the phosphonateA30.10.

For example, condensation between dimethyl succinate and methyl1-methylimidazole-4,5-dicarboxylate A30.11 (Eqypt. J. Chem., 1985, 28,139) yields, after protection of the phenolic hydroxyl groups,4,7-bis-methoxymethoxy-1-methyl-1H-benzoimidazole-5,6-dicarboxylic aciddimethyl ester A30.12. Partial hydrolysis then gives the monocarboxylicacid A30.13, and this compound is subjected to Arndt Eisterthomologation to give the corresponding acetic acid A30.14. Thecarboxylic acid is coupled, in the presence of dicyclohexylcarbodiimide, with cyclohexylmethylamine A30.15 to give the amideA30.16. Cyclization is effected as described above to prepare6-cyclohexylmethyl-4,9-bis-methoxymethoxy-1-methyl-1,5,6,8-tetrahydro-1,3,6-triaza-cyclopenta[b]naphthalen-7-oneA30.17. The product is then reacted in dioxan solution with a dialkylbromoethyl phosphonate A30.18 (Aldrich) and lithiumhexamethyldisilazide, to give after deprotection the phosphonate A30.19.

Using the above procedures, but employing, in place of the startingmaterials A30.1 and A30.11, different starting materials A30.1 andA30.2, and/or different phosphonates A30.9, the corresponding productsA30.10 are obtained.

Preparation of the Intermediate Phosphonate Esters IVbb.

Schemes A31 and A32 illustrates the preparation of phosphonate esters ofstructure IVbb. Scheme A31 illustrates the preparation of phosphonateesters in which the phosphonate is attached by means of a variablecarbon linkage linkage. In this procedure, the doubly protected phenolA29.3 is selectively deprotected to give the phenol A31.1. The productis converted into the triflate A31.2 and this material is reacted with adialkyl hydroxy, mercapto or amino-substituted phosphonate A31.3, inwhich the group R is an acyclic or cyclic saturated or unsaturatedalkylene, or aryl, aralkyl or heteroaryl moiety, in the presence of abase, as described in Scheme A8, to afford the displacement productA31.4, which upon deprotection gives the phenol A31.5.

For example, 2-naphthylmethylsuccinimide A31.6 is reacted with dimethylpyrimidine 4,5-dicarboxylate A31.7 (Chem. Ber., 1975, 108, 3877) toafford after differential protection, as describe in Scheme 1 andExample 2 and triflate formation, trifluoro-methanesulfonic acid7-naphthalen-2-ylmethyl-6,8-dioxo-9-triisopropylsilanyloxy-7,8-dihydro-6H-pyrrolo[3,4-g]quinazolin-5-ylester A31.8. The compound is then reacted with a dialkyl 3-hydroxyphenylphosphonate A31.9 (Aurora) and triethylamine in dichloromethane to givethe phosphonate A31.10.

Using the above procedures, but employing, in place of the startingmaterials A31.6 and A31.7, different starting materials A29.3 and/ordifferent phosphonates A31.3, the corresponding products A31.5 areobtained.

Scheme A32 depicts the preparation of phosphonate esters of structureVbb in which the phosphonate is attached by means of an ether linkage.In this procedure, dimethyl succinate A32.1 is condensed under basicconditions, with a heterocyclic dicarboxylic ester A32.2 to afford thebicyclic product A32.3. Hydrolysis of the ester groups, followed byanhydride formation and selective protection of the phenolic hydroxylgroups, then gives the product A32.4. The anhydride is then reacted, asdescribed with the substituted hydrazine A32.5, to yield the tricyclicproduct A32.6. Selective deprotection then affords the phenol A32.7, andthis compound is then reacted with a dialkyl hydroxy-substitutedphosphonate A32.8, in which the group R is an acyclic or cyclicsaturated or unsaturated alkylene, or aryl, aralkyl or heteroarylmoiety, under the conditions of the Mitsonobu reaction, as described inScheme A6, to form after deprotection the phenol A32.9.

For example, condensation between dimethyl succinate and dimethyl1,3,4-triazine-5,6-dicarboxylate A32.10 (J. Org. Chem., 23, 1931, 1958)affords after selective silylation, following a procedure similar toExample 12,6-(4-fluoro-benzyl)-9-hydroxy-10-triisopropylsilanyloxy-6,7-dihydro-1,2,4,6,7-pentaaza-anthracene-5,8-dioneA32.11. The product is then reacted in tetrahydrofuran with a dialkylhydroxyethyl phosphonate A32.12, (Epsilon) diethyl azodicarboxylate andtriphenyl phosphine to yield after deprotection the phenolic phosphonateA32.13.

Using the above procedures, but employing, in place of the startingmaterial A32.10 different starting materials A32.2 and/or differentphosphonates A32.8, the corresponding products A32.9 are obtained.

Preparation of the Intermediate Phosphonate Esters IVcc.

Scheme A33 illustrates the preparation of phosphonate esters ofstructure IVcc in which the phosphonate is attached by means of a carbonlinkage. In this procedure, a substituted succinimide A33.1 is reactedwith a heterocyclic diester A33.2 to afford after protection thebicyclic product A33.3. The amino group of the product is then alkylatedby reaction with a dialkyl bromo-substituted phosphonate A33.4 to yieldafter deprotection the phenolic phosphonate A33.5.

For example,1-(6-fluoro-1,2,3,4-tetrahydro-naphthalen-1-yl)-pyrrolidine-2,5-dioneA33.6, prepared by the reaction of2-amino-7-fluoro-1,2,3,4-tetrahydronaphthalene (U.S. Pat. No. 5,538,988)and succinic anhydride, is reacted with dimethyl1,2,3-triazole-4,5-dicarboxylate A33.7 (Interchim) to afford aftersilylation of the phenolic hydroxyl groups6-(6-fluoro-1,2,3,4-tetrahydro-naphthalen-1-yl)-4,8-bis-triisopropylsilanyloxy-1H-pyrrolo[3′,4′:4,5]benzo[1,2-d][1,2,3]triazole-5,7-dioneA33.8. The product is then reacted, in dimethylformamide solution withone molar equivalent of sodium hydride and a dialkyl 4-bromobutylphosphonate A33.9 (Syn., 1994, 9, 909) to afford after deprotection thephosphonate A33.10.

Using the above procedures, but employing, in place of the startingmaterials A33.6 and A33.7 different starting materials A33.1 and A33.2and/or different phosphonates A33.4, the corresponding products A33.5are obtained.

Interconversions of the Phosphonates R-link-P(O)(OR⁵)₂,R-link-P(O)(OR⁵)(OH) and R-link-P(O)(OH)₂.

Schemes A1-A33 described the preparations of phosphonate esters of thegeneral structure R-link-P(O)(OR⁵)₂, in which the groups R⁵ may be thesame or different. The R⁵ groups attached to a phosphonate estersIaa-IVcc, or to precursors thereto, may be changed using establishedchemical transformations. The interconversions reactions of phosphonatesare illustrated in Scheme A34. The group R in Scheme A34 represents thesubstructure to which the substituent link-P(O)(OR⁵)₂ is attached,either in the compounds Iaa-Ivcc or in precursors thereto. The R⁵ groupmay be changed, using the procedures described below, either in theprecursor compounds, or in the esters Iaa-IVcc. The methods employed fora given phosphonate transformation depend on the nature of thesubstituent R⁵. The preparation and hydrolysis of phosphonate esters isdescribed in Organic Phosphorus Compounds, G. M. Kosolapoff, L. Maeir,eds, Wiley, 1976, p. 9ff.

The conversion of a phosphonate diester A34.1 into the correspondingphosphonate monoester A34.2 (Scheme A34, Reaction 1) can be accomplishedby a number of methods. For example, the ester A34.1 in which R⁵ is anaralkyl group such as benzyl, can be converted into the monoestercompound A34.2 by reaction with a tertiary organic base such asdiazabicyclooctane (DABCO) or quinuclidine, as described in J. Org.Chem., 1995, 60, 2946. The reaction is performed in an inert hydrocarbonsolvent such as toluene or xylene, at about 11° C. The conversion of thediester A34.1 in which R⁵ is an aryl group such as phenyl, or an alkenylgroup such as allyl, into the monoester A34.2 can be effected bytreatment of the ester A34.1 with a base such as aqueous sodiumhydroxide in acetonitrile or lithium hydroxide in aqueoustetrahydrofuran. Phosphonate diesters A34.1 in which one of the groupsR⁵ is aralkyl, such as benzyl, and the other is alkyl, can be convertedinto the monoesters A34.2 in which R⁵ is alkyl by hydrogenation, forexample using a palladium on carbon catalyst. Phosphonate diesters inwhich both of the groups R⁵ are alkenyl, such as allyl, can be convertedinto the monoester A34.2 in which R⁵ is alkenyl, by treatment withchlorotris(triphenylphosphine)rhodium (Wilkinson's catalyst) in aqueousethanol at reflux, optionally in the presence of diazabicyclooctane, forexample by using the procedure described in J. Org. Chem., 38, 3224,1973 for the cleavage of allyl carboxylates.

The conversion of a phosphonate diester A34.1 or a phosphonate monoesterA34.2 into the corresponding phosphonic acid A34.3 (Scheme A34,Reactions 2 and 3) can effected by reaction of the diester or themonoester with trimethylsilyl bromide, as described in J. Chem. Soc.,Chem. Comm., 739, 1979. The reaction is conducted in an inert solventsuch as, for example, dichloromethane, optionally in the presence of asilylating agent such as bis(trimethylsilyl)trifluoroacetamide, atambient temperature. A phosphonate monoester A34.2 in which R⁵ isaralkyl such as benzyl, can be converted into the correspondingphosphonic acid A34.3 by hydrogenation over a palladium catalyst, or bytreatment with hydrogen chloride in an ethereal solvent such as dioxan.A phosphonate monoester A34.2 in which R⁵ is alkenyl such as, forexample, allyl, can be converted into the phosphonic acid A34.3 byreaction with Wilkinson's catalyst in an aqueous organic solvent, forexample in 15% aqueous acetonitrile, or in aqueous ethanol, for exampleusing the procedure described in Helv. Chim. Acta., 68, 618, 1985.Palladium catalyzed hydrogenolysis of phosphonate esters A34.1 in whichR⁵ is benzyl is described in J. Org. Chem., 24,434, 1959.Platinum-catalyzed hydrogenolysis of phosphonate esters A34.1 in whichR⁵ is phenyl is described in J. Am. Chem. Soc., 78, 2336, 1956.

The conversion of a phosphonate monoester A34.2 into a phosphonatediester A34.1 (Scheme A34, Reaction 4) in which the newly introduced R⁵group is alkyl, aralkyl, haloalkyl such as chloroethyl, or aralkyl canbe effected by a number of reactions in which the substrate A34.2 isreacted with a hydroxy compound R⁵OH, in the presence of a couplingagent. Suitable coupling agents are those employed for the preparationof carboxylate esters, and include a carbodiimide such asdicyclohexylcarbodiimide, in which case the reaction is preferablyconducted in a basic organic solvent such as pyridine, or(benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate(PYBOP, Sigma), in which case the reaction is performed in a polarsolvent such as dimethylformamide, in the presence of a tertiary organicbase such as diisopropylethylamine, or Aldrithiol-2 (Aldrich) in whichcase the reaction is conducted in a basic solvent such as pyridine, inthe presence of a triaryl phosphine such as triphenylphosphine.Alternatively, the conversion of the phosphonate monoester A34.2 to thediester A34.1 can be effected by the use of the Mitsonobu reaction, asdescribed above (Scheme A6). The substrate is reacted with the hydroxycompound R⁵OH, in the presence of diethyl azodicarboxylate and atriarylphosphine such as triphenyl phosphine. Alternatively, thephosphonate monoester A34.2 can be transformed into the phosphonatediester A34.1, in which the introduced R⁵ group is alkenyl or aralkyl,by reaction of the monoester with the halide R⁵Br, in which R⁵ is asalkenyl or aralkyl. The alkylation reaction is conducted in a polarorganic solvent such as dimethylformamide or acetonitrile, in thepresence of a base such as cesium carbonate. Alternatively, thephosphonate monoester can be transformed into the phosphonate diester ina two step procedure. In the first step, the phosphonate monoester A34.2is transformed into the chloro analog RP(O)(OR⁵)Cl by reaction withthionyl chloride or oxalyl chloride and the like, as described inOrganic Phosphorus Compounds, G. M. Kosolapoff, L. Maeir, eds, Wiley,1976, p. 17, and the thus-obtained product RP(O)(OR⁵)Cl is then reactedwith the hydroxy compound R⁵OH, in the presence of a base such astriethylamine, to afford the phosphonate diester A34.1.

A phosphonic acid R-link-P(O)(OH)₂ can be transformed into a phosphonatemonoester RP(O)(OR⁵)(OH) (Scheme A34, Reaction 5) by means of themethods described above of for the preparation of the phosphonatediester R-link-P(O)(OR⁵)₂ A34.1, except that only one molar proportionof the component R⁵OH or R⁵Br is employed.

A phosphonic acid R-link-P(O)(OH)₂ A34.3 can be transformed into aphosphonate diester R-link-P(O)(OR⁵)₂ A34.1 (Scheme A34, Reaction 6) bya coupling reaction with the hydroxy compound R⁵OH, in the presence of acoupling agent such as Aldrithiol-2 (Aldrich) and triphenylphosphine.The reaction is conducted in a basic solvent such as pyridine.Alternatively, phosphonic acids A34.3 can be transformed into phosphonicesters A34.1 in which R⁵ is aryl, by means of a coupling reactionemploying, for example, dicyclohexylcarbodiimide in pyridine at ca 70°C. Alternatively, phosphonic acids A34.3 can be transformed intophosphonic esters A34.1 in which R⁵ is alkenyl, by means of analkylation reaction. The phosphonic acid is reacted with the alkenylbromide R⁵Br in a polar organic solvent such as acetonitrile solution atreflux temperature, the presence of a base such as cesium carbonate, toafford the phosphonic ester A34.1.

Preparation of Carboalkoxy-Substituted Phosphonate Bisamidates,Monoamidates, Diesters and Monoesters.

A number of methods are available for the conversion of phosphonic acidsinto amidates and esters. In one group of methods, the phosphonic acidis either converted into an isolated activated intermediate such as aphosphoryl chloride, or the phosphonic acid is activated in situ forreaction with an amine or a hydroxy compound.

The conversion of phosphonic acids into phosphoryl chlorides isaccomplished by reaction with thionyl chloride, for example as describedin J. Gen. Chem. USSR, 1983, 53, 480, Zh. Obschei Khim., 1958, 28, 1063,or J. Org. Chem., 1994, 59, 6144, or by reaction with oxalyl chloride,as described in J. Am. Chem. Soc., 1994, 116, 3251, or J. Org. Chem.,1994, 59, 6144, or by reaction with phosphorus pentachloride, asdescribed in J. Org. Chem., 2001, 66, 329, or in J. Med. Chem., 1995,38, 1372. The resultant phosphoryl chlorides are then reacted withamines or hydroxy compounds in the presence of a base to afford theamidate or ester products.

Phosphonic acids are converted into activated imidazolyl derivatives byreaction with carbonyl diimidazole, as described in J. Chem. Soc., Chem.Comm., 1991, 312, or Nucleosides Nucleotides 2000, 19, 1885. Activatedsulfonyloxy derivatives are obtained by the reaction of phosphonic acidswith trichloromethylsulfonyl chloride, as described in J. Med. Chem.1995, 38, 4958, or with triisopropylbenzenesulfonyl chloride, asdescribed in Tet. Lett., 1996, 7857, or Bioorg. Med. Chem. Lett., 1998,8, 663. The activated sulfonyloxy derivatives are then reacted withamines or hydroxy compounds to afford amidates or esters.

Alternatively, the phosphonic acid and the amine or hydroxy reactant arecombined in the presence of a diimide coupling agent. The preparation ofphosphonic amidates and esters by means of coupling reactions in thepresence of dicyclohexyl carbodiimide is described, for example, in J.Chem. Soc., Chem. Comm., 1991, 312, or J. Med. Chem., 1980, 23, 1299 orColl. Czech. Chem. Comm., 1987, 52, 2792. The use of ethyldimethylaminopropyl carbodiimide for activation and coupling ofphosphonic acids is described in Tet. Lett., 2001, 42, 8841, orNucleosides Nucleotides, 2000, 19, 1885.

A number of additional coupling reagents have been described for thepreparation of amidates and esters from phosphonic acids. The agentsinclude Aldrithiol-2, and PYBOP and BOP, as described in J. Org. Chem.,1995, 60, 5214, and J. Med. Chem., 1997, 40, 3842,mesitylene-2-sulfonyl-3-nitro-1,2,4-triazole (MSNT), as described in J.Med. Chem., 1996, 39, 4958, diphenylphosphoryl azide, as described in J.Org. Chem., 1984, 49, 1158,1-(2,4,6-triisopropylbenzenesulfonyl-3-nitro-1,2,4-triazole (TPSNT) asdescribed in Bioorg. Med. Chem. Lett., 1998, 8, 1013,bromotris(dimethylamino)phosphonium hexafluorophosphate (BroP), asdescribed in Tet. Lett., 1996, 37, 3997,2-chloro-5,5-dimethyl-2-oxo-1,3,2-dioxaphosphinane, as described inNucleosides Nucleotides 1995, 14, 871, and diphenyl chlorophosphate, asdescribed in J. Med. Chem., 1988, 31, 1305.

Phosphonic acids are converted into amidates and esters by means of theMitsonobu reaction, in which the phosphonic acid and the amine orhydroxy reactant are combined in the presence of a triaryl phosphine anda dialkyl azodicarboxylate. The procedure is described in Org. Lett.,2001, 3, 643, or J. Med. Chem., 1997, 40, 3842.

Phosphonic esters are also obtained by the reaction between phosphonicacids and halo compounds, in the presence of a suitable base. The methodis described, for example, in Anal. Chem., 1987, 59, 1056, or J. Chem.Soc. Perkin Trans., I, 1993, 19, 2303, or J. Med. Chem., 1995, 38, 1372,or Tet. Lett., 2002, 43, 1161.

Schemes 1-5 illustrate the conversion of phosphonate esters andphosphonic acids into carboalkoxy-substituted phosphorobisamidates(Scheme 1), phosphoroamidates (Scheme 2), phosphonate monoesters (Scheme3) and phosphonate diesters, (Scheme 4)

Scheme 1 illustrates various methods for the conversion of phosphonatediesters 1.1 into phosphorobisamidates 1.5. The diester 1.1, prepared asdescribed previously, is hydrolyzed, either to the monoester 1.2 or tothe phosphonic acid 1.6. The methods employed for these transformationsare described above. The monoester 1.2 is converted into the monoamidate1.3 by reaction with an aminoester 1.9, in which the group R² is H oralkyl, the group R⁴ is an alkylene moiety such as, for example, CHCH₃,CHPr¹, CH(CH₂Ph), CH₂CH(CH₃) and the like, or a group present in naturalor modified amino acids, and the group R⁵ is alkyl. The reactants arecombined in the presence of a coupling agent such as a carbodiimide, forexample dicyclohexyl carbodiimide, as described in J. Am. Chem. Soc.,1957, 79, 3575, optionally in the presence of an activating agent suchas hydroxybenztriazole, to yield the amidate product 1.3. Theamidate-forming reaction is also effected in the presence of couplingagents such as BOP, as described in J. Org. Chem., 1995, 60, 5214,Aldrithiol, PYBOP and similar coupling agents used for the preparationof amides and esters. Alternatively, the reactants 1.2 and 1.9 aretransformed into the monoamidate 1.3 by means of a Mitsonobu reaction.The preparation of amidates by means of the Mitsonobu reaction isdescribed in J. Med. Chem., 1995, 38, 2742. Equimolar amounts of thereactants are combined in an inert solvent such as tetrahydrofuran inthe presence of a triaryl phosphine and a dialkyl azodicarboxylate. Thethus-obtained monoamidate ester 1.3 is then transformed into amidatephosphonic acid 1.4. The conditions used for the hydrolysis reactiondepend on the nature of the R¹ group, as described previously. Thephosphonic acid amidate 1.4 is then reacted with an aminoester 1.9, asdescribed above, to yield the bisamidate product 1.5, in which the aminosubstituents are the same or different.

An example of this procedure is shown in Scheme 1, Example 1. In thisprocedure, a dibenzyl phosphonate 1.14 is reacted withdiazabicyclooctane (DABCO) in toluene at reflux, as described in J. Org.Chem., 1995, 60, 2946, to afford the monobenzyl phosphonate 1.15. Theproduct is then reacted with equimolar amounts of ethyl alaninate 1.16and dicyclohexyl carbodiimide in pyridine, to yield the amidate product1.17. The benzyl group is then removed, for example by hydrogenolysisover a palladium catalyst, to give the monoacid product 1.18. Thiscompound is then reacted in a Mitsonobu reaction with ethyl leucinate1.19, triphenyl phosphine and diethylazodicarboxylate, as described inJ. Med. Chem., 1995, 38, 2742, to produce the bisamidate product 1.20.

Using the above procedures, but employing, in place of ethyl leucinate1.19 or ethyl alaninate 1.16, different aminoesters 1.9, thecorresponding products 1.5 are obtained.

Alternatively, the phosphonic acid 1.6 is converted into the bisamidate1.5 by use of the coupling reactions described above. The reaction isperformed in one step, in which case the nitrogen-related substituentspresent in the product 1.5 are the same, or in two steps, in which casethe nitrogen-related substituents can be different.

An example of the method is shown in Scheme 1, Example 2. In thisprocedure, a phosphonic acid 1.6 is reacted in pyridine solution withexcess ethyl phenylalaninate 1.21 and dicyclohexylcarbodiimide, forexample as described in J. Chem. Soc., Chem. Comm., 1991, 1063, to givethe bisamidate product 1.22.

Using the above procedures, but employing, in place of ethylphenylalaninate, different aminoesters 1.9, the corresponding products1.5 are obtained.

As a further alternative, the phosphonic acid 1.6 is converted into themono or bis-activated derivative 1.7, in which Lv is a leaving groupsuch as chloro, imidazolyl, triisopropylbenzenesulfonyloxy etc. Theconversion of phosphonic acids into chlorides 1.7 (Lv=Cl) is effected byreaction with thionyl chloride or oxalyl chloride and the like, asdescribed in Organic Phosphorus Compounds, G. M. Kosolapoff L. Maeir,eds, Wiley, 1976, p. 17. The conversion of phosphonic acids intomonoimidazolides 1.7 (Lv=imidazolyl) is described in J. Med. Chem.,2002, 45, 1284 and in J. Chem. Soc. Chem. Comm., 1991, 312.Alternatively, the phosphonic acid is activated by reaction withtriisopropylbenzenesulfonyl chloride, as described in Nucleosides andNucleotides, 2000, 10, 1885. The activated product is then reacted withthe aminoester 1.9, in the presence of a base, to give the bisamidate1.5. The reaction is performed in one step, in which case the nitrogensubstituents present in the product 1.5 are the same, or in two steps,via the intermediate 1.11, in which case the nitrogen substituents canbe different.

Examples of these methods are shown in Scheme 1, Examples 3 and 5. Inthe procedure illustrated in Scheme 1, Example 3, a phosphonic acid 1.6is reacted with ten molar equivalents of thionyl chloride, as describedin Zh. Obschei Khim., 1958, 28, 1063, to give the dichloro compound1.23. The product is then reacted at reflux temperature in a polaraprotic solvent such as acetonitrile, and in the presence of a base suchas triethylamine, with butyl serinate 1.24 to afford the bisamidateproduct 1.25.

Using the above procedures, but employing, in place of butyl serinate1.24, different aminoesters 1.9, the corresponding products 1.5 areobtained.

In the procedure illustrated in Scheme 1, Example 5, the phosphonic acid1.6 is reacted, as described in J. Chem. Soc. Chem. Comm., 1991, 312,with carbonyl diimidazole to give the imidazolide 1.32. The product isthen reacted in acetonitrile solution at ambient temperature, with onemolar equivalent of ethyl alaninate 1.33 to yield the monodisplacementproduct 1.34. The latter compound is then reacted with carbonyldiimidazole to produce the activated intermediate 1.35, and the productis then reacted, under the same conditions, with ethyl N-methylalaninate1.33a to give the bisamidate product 1.36.

Using the above procedures, but employing, in place of ethyl alaninate1.33 or ethyl N-methylalaninate 1.33a, different aminoesters 1.9, thecorresponding products 1.5 are obtained.

The intermediate monoamidate 1.3 is also prepared from the monoester 1.2by first converting the monoester into the activated derivative 1.8 inwhich Lv is a leaving group such as halo, imidazolyl etc, using theprocedures described above. The product 1.8 is then reacted with anaminoester 1.9 in the presence of a base such as pyridine, to give anintermediate monoamidate product 1.3. The latter compound is thenconverted, by removal of the R¹ group and coupling of the product withthe aminoester 1.9, as described above, into the bisamidate 1.5.

An example of this procedure, in which the phosphonic acid is activatedby conversion to the chloro derivative 1.26, is shown in Scheme 1,Example 4. In this procedure, the phosphonic monobenzyl ester 1.15 isreacted, in dichloromethane, with thionyl chloride, as described in Tet.Let., 1994, 35, 4097, to afford the phosphoryl chloride 1.26. Theproduct is then reacted in acetonitrile solution at ambient temperaturewith one molar equivalent of ethyl 3-amino-2-methylpropionate 1.27 toyield the monoamidate product 1.28. The latter compound is hydrogenatedin ethylacetate over a 5% palladium on carbon catalyst to produce themonoacid product 1.29. The product is subjected to a Mitsonobu couplingprocedure, with equimolar amounts of butyl aluminate 1.30, triphenylphosphine, diethylazodicarboxylate and triethylamine in tetrahydrofuran,to give the bisamidate product 1.31.

Using the above procedures, but employing, in place of ethyl3-amino-2-methylpropionate 1.27 or butyl alaninate 1.30, differentaminoesters 1.9, the corresponding products 1.5 are obtained.

The activated phosphonic acid derivative 1.7 is also converted into thebisamidate 1.5 via the diamino compound 1.10. The conversion ofactivated phosphonic acid derivatives such as phosphoryl chlorides intothe corresponding amino analogs 1.10, by reaction with ammonia, isdescribed in Organic Phosphorus Compounds, G. M. Kosolapoff, L. Maeir,eds, Wiley, 1976. The diamino compound 1.10 is then reacted at elevatedtemperature with a haloester 1.12, in a polar organic solvent such asdimethylformamide, in the presence of a base such asdimethylaminopyridine or potassium carbonate, to yield the bisamidate1.5.

An example of this procedure is shown in Scheme 1, Example 6. In thismethod, a dichlorophosphonate 1.23 is reacted with ammonia to afford thediamide 1.37. The reaction is performed in aqueous, aqueous alcoholic oralcoholic solution, at reflux temperature. The resulting diaminocompound is then reacted with two molar equivalents of ethyl2-bromo-3-methylbutyrate 1.38, in a polar organic solvent such asN-methylpyrrolidinone at ca. 150° C., in the presence of a base such aspotassium carbonate, and optionally in the presence of a catalyticamount of potassium iodide, to afford the bisamidate product 1.39.

Using the above procedures, but employing, in place of ethyl2-bromo-3-methylbutyrate 1.38, different haloesters 1.12 thecorresponding products 1.5 are obtained.

The procedures shown in Scheme 1 are also applicable to the preparationof bisamidates in which the aminoester moiety incorporates differentfunctional groups, Scheme 1, Example 7 illustrates the preparation ofbisamidates derived from tyrosine. In this procedure, themonoimidazolide 1.32 is reacted with propyl tyrosinate 1.40, asdescribed in Example 5, to yield the monoamidate 1.41. The product isreacted with carbonyl diimidazole to give the imidazolide 1.42, and thismaterial is reacted with a further molar equivalent of propyl tyrosinateto produce the bisamidate product 1.43.

Using the above procedures, but employing, in place of propyl tyrosinate1.40, different aminoesters 1.9, the corresponding products 1.5 areobtained. The aminoesters employed in the two stages of the aboveprocedure can be the same or different, so that bisamidates with thesame or different amino substituents are prepared.

Scheme 2 illustrates methods for the preparation of phosphonatemonoamidates.

In one procedure, a phosphonate monoester 1.1 is converted, as describedin Scheme 1, into the activated derivative 1.8. This compound is thenreacted, as described above, with an aminoester 1.9, in the presence ofa base, to afford the monoamidate product 2.1.

The procedure is illustrated in Scheme 2, Example 1. In this method, amonophenyl phosphonate 2.7 is reacted with, for example, thionylchloride, as described in J. Gen. Chem. USSR., 1983, 32, 367, to givethe chloro product 2.8. The product is then reacted, as described inScheme 1, with ethyl alaninate 2.9, to yield the amidate 2.10.

Using the above procedures, but employing, in place of ethyl alaninate2.9, different aminoesters 1.9, the corresponding products 2.1 areobtained.

Alternatively, the phosphonate monoester 1.1 is coupled, as described inScheme 1, with an aminoester 1.9 to produce the amidate 2.1. Ifnecessary, the R¹ substituent is then altered, by initial cleavage toafford the phosphonic acid 2.2. The procedures for this transformationdepend on the nature of the R¹ group, and are described above. Thephosphonic acid is then transformed into the ester amidate product 2.3,by reaction with the hydroxy compound R³OH, in which the group R³ isaryl, heteroaryl, alkyl, cycloalkyl, haloalkyl etc, using the samecoupling procedures (carbodiimide, Aldrithiol-2, PYBOP, Mitsonobureaction etc) described in Scheme 1 for the coupling of amines andphosphonic acids.

Examples of this method are shown in Scheme 2, Examples and 2 and 3. Inthe sequence shown in Example 2, a monobenzyl phosphonate 2.11 istransformed by reaction with ethyl alaninate, using one of the methodsdescribed above, into the monoamidate 2.12. The benzyl group is thenremoved by catalytic hydrogenation in ethylacetate solution over a 5%palladium on carbon catalyst, to afford the phosphonic acid amidate2.13. The product is then reacted in dichloromethane solution at ambienttemperature with equimolar amounts of1-(dimethylaminopropyl)-3-ethylcarbodiimide and trifluoroethanol 2.14,for example as described in Tet. Lett., 2001, 42, 8841, to yield theamidate ester 2.15.

In the sequence shown in Scheme 2, Example 3, the monoamidate 2.13 iscoupled, in tetrahydrofuran solution at ambient temperature, withequimolar amounts of dicyclohexyl carbodiimide and4-hydroxy-N-methylpiperidine 2.16, to produce the amidate ester product2.17.

Using the above procedures, but employing, in place of the ethylalaninate product 2.12 different monoacids 2.2, and in place oftrifluoroethanol 2.14 or 4-hydroxy-N-methylpiperidine 2.16, differenthydroxy compounds R³OH, the corresponding products 2.3 are obtained.

Alternatively, the activated phosphonate ester 1.8 is reacted withammonia to yield the amidate 2.4. The product is then reacted, asdescribed in Scheme 1, with a haloester 2.5, in the presence of a base,to produce the amidate product 2.6. If appropriate, the nature of the R¹group is changed, using the procedures described above, to give theproduct 2.3. The method is illustrated in Scheme 2, Example 4. In thissequence, the monophenyl phosphoryl chloride 2.18 is reacted, asdescribed in Scheme 1, with ammonia, to yield the amino product 2.19.This material is then reacted in N-methylpyrrolidinone solution at 170°C. with butyl 2-bromo-3-phenylpropionate 2.20 and potassium carbonate,to afford the amidate product 2.21.

Using these procedures, but employing, in place of butyl2-bromo-3-phenylpropionate 2.20, different haloesters 2.5, thecorresponding products 2.6 are obtained.

The monoamidate products 2.3 are also prepared from the doubly activatedphosphonate derivatives 1.7. In this procedure, examples of which aredescribed in Synlett., 1998, 1, 73, the intermediate 1.7 is reacted witha limited amount of the aminoester 1.9 to give the mono-displacementproduct 1.11. The latter compound is then reacted with the hydroxycompound R³OH in a polar organic solvent such as dimethylformamide, inthe presence of a base such as diisopropylethylamine, to yield themonoamidate ester 2.3.

The method is illustrated in Scheme 2, Example 5. In this method, thephosphoryl dichloride 2.22 is reacted in dichloromethane solution withone molar equivalent of ethyl N-methyl tyrosinate 2.23 anddimethylaminopyridine, to generate the monoamidate 2.24. The product isthen reacted with phenol 2.25 in dimethylformamide containing potassiumcarbonate, to yield the ester amidate product 2.26.

Using these procedures, but employing, in place of ethyl N-methyltyrosinate 2.23 or phenol 2.25, the aminoesters 1.9 and/or the hydroxycompounds R³OH, the corresponding products 2.3 are obtained.

Scheme 3 illustrates methods for the preparation ofcarboalkoxy-substituted phosphonate diesters in which one of the estergroups incorporates a carboalkoxy substituent.

In one procedure, a phosphonate monoester 1.1, prepared as describedabove, is coupled, using one of the methods described above, with ahydroxyester 3.1, in which the groups R⁴ and R⁵ are as described inScheme 1. For example, equimolar amounts of the reactants are coupled inthe presence of a carbodiimide such as dicyclohexyl carbodiimide, asdescribed in Aust. J. Chem., 1963, 609, optionally in the presence ofdimethylaminopyridine, as described in Tet., 1999, 55, 12997. Thereaction is conducted in an inert solvent at ambient temperature.

The procedure is illustrated in Scheme 3, Example 1. In this method, amonophenyl phosphonate 3.9 is coupled, in dichloromethane solution inthe presence of dicyclohexyl carbodiimide, with ethyl3-hydroxy-2-methylpropionate 3.10 to yield the phosphonate mixed diester3.11.

Using this procedure, but employing, in place of ethyl3-hydroxy-2-methylpropionate 3.10, different hydroxyesters 3.1, thecorresponding products 3.2 are obtained.

The conversion of a phosphonate monoester 1.1 into a mixed diester 3.2is also accomplished by means of a Mitsonobu coupling reaction with thehydroxyester 3.1, as described in Org. Lett., 2001, 643. in this method,the reactants 1.1 and 3.1 are combined in a polar solvent such astetrahydrofuran, in the presence of a triarylphosphine and a dialkylazodicarboxylate, to give the mixed diester 3.2. The R¹ substituent isvaried by cleavage, using the methods described previously, to affordthe monoacid product 3.3. The product is then coupled, for example usingmethods described above, with the hydroxy compound R³OH, to give thediester product 3.4.

The procedure is illustrated in Scheme 3, Example 2. In this method, amonoallyl phosphonate 3.12 is coupled in tetrahydrofuran solution, inthe presence of triphenylphosphine and diethylazodicarboxylate, withethyl lactate 3.13 to give the mixed diester 3.14. The product isreacted with tris(triphenylphosphine) rhodium chloride (Wilkinsoncatalyst) in acetonitrile, as described previously, to remove the allylgroup and produce the monoacid product 3.15. The latter compound is thencoupled, in pyridine solution at ambient temperature, in the presence ofdicyclohexyl carbodiimide, with one molar equivalent of3-hydroxypyridine 3.16 to yield the mixed diester 3.17.

Using the above procedures, but employing, in place of the ethyl lactate3.13 or 3-hydroxypyridine, a different hydroxyester 3.1 and/or adifferent hydroxy compound R³OH, the corresponding products 3.4 areobtained.

The mixed diesters 3.2 are also obtained from the monoesters 1.1 via theintermediacy of the activated monoesters 3.5. In this procedure, themonoester 1.1 is converted into the activated compound 3.5 by reactionwith, for example, phosphorus pentachloride, as described in J. Org.Chem., 2001, 66, 329, or with thionyl chloride or oxalyl chloride(Lv=Cl), or with triisopropylbenzenesulfonyl chloride in pyridine, asdescribed in Nucleosides and Nucleotides, 2000, 19, 1885, or withcarbonyl diimidazole, as described in J. Med. Chem., 2002, 45, 1284. Theresultant activated monoester is then reacted with the hydroxyester 3.1,as described above, to yield the mixed diester 3.2.

The procedure is illustrated in Scheme 3, Example 3. In this sequence, amonophenyl phosphonate 3.9 is reacted, in acetonitrile solution at 70°C., with ten equivalents of thionyl chloride, so as to produce thephosphoryl chloride 3.19. The product is then reacted with ethyl4-carbamoyl-2-hydroxybutyrate 3.20 in dichloromethane containingtriethylamine, to give the mixed diester 3.21.

Using the above procedures, but employing, in place of ethyl4-carbamoyl-2-hydroxybutyrate 3.20, different hydroxyesters 3.1, thecorresponding products 3.2 are obtained.

The mixed phosphonate diesters are also obtained by an alternative routefor incorporation of the R³O group into intermediates 3.3 in which thehydroxyester moiety is already incorporated. In this procedure, themonoacid intermediate 3.3 is converted into the activated derivative 3.6in which Lv is a leaving group such as chloro, imidazole, and the like,as previously described. The activated intermediate is then reacted withthe hydroxy compound R³OH, in the presence of a base, to yield the mixeddiester product 3.4.

The method is illustrated in Scheme 3, Example 4. In this sequence, thephosphonate monoacid 3.22 is reacted with trichloromethanesulfonylchloride in tetrahydrofuran containing collidine, as described in J.Med. Chem., 1995, 38, 4648, to produce the trichloromethanesulfonyloxyproduct 3.23. This compound is reacted with 3-(morpholinomethyl)phenol3.24 in dichloromethane containing triethylamine, to yield the mixeddiester product 3.25.

Using the above procedures, but employing, in place of with3-(morpholinomethyl)phenol 3.24, different carbinols R³OH, thecorresponding products 3.4 are obtained.

The phosphonate esters 3.4 are also obtained by means of alkylationreactions performed on the monoesters 1.1. The reaction between themonoacid 1.1 and the haloester 3.7 is performed in a polar solvent inthe presence of a base such as diisopropylethylamine, as described inAnal. Chem., 1987, 59, 1056, or triethylamine, as described in J. Med.Chem., 1995, 38, 1372, or in a non-polar solvent such as benzene, in thepresence of 18-crown-6, as described in Syn. Comm., 1995, 25, 3565.

The method is illustrated in Scheme 3, Example 5. In this procedure, themonoacid 3.26 is reacted with ethyl 2-bromo-3-phenylpropionate 3.27 anddiisopropylethylamine in dimethylformamide at 80° C. to afford the mixeddiester product 3.28.

Using the above procedure, but employing, in place of ethyl2-bromo-3-phenylpropionate 3.27, different haloesters 3.7, thecorresponding products 3.4 are obtained.

Scheme 4 illustrates methods for the preparation of phosphonate diestersin which both the ester substituents incorporate carboalkoxy groups.

The compounds are prepared directly or indirectly from the phosphonicacids 1.6. In one alternative, the phosphonic acid is coupled with thehydroxyester 4.2, using the conditions described previously in Schemes1-3, such as coupling reactions using dicyclohexyl carbodiimide orsimilar reagents, or under the conditions of the Mitsonobu reaction, toafford the diester product 4.3 in which the ester substituents areidentical.

This method is illustrated in Scheme 4, Example 1. In this procedure,the phosphonic acid 1.6 is reacted with three molar equivalents of butyllactate 4.5 in the presence of Aldrithiol-2 and triphenyl phosphine inpyridine at ca. 70° C., to afford the diester 4.6.

Using the above procedure, but employing, in place of butyl lactate 4.5,different hydroxyesters 4.2, the corresponding products 4.3 areobtained.

Alternatively, the diesters 4.3 are obtained by alkylation of thephosphonic acid 1.6 with a haloester 4.1. The alkylation reaction isperformed as described in Scheme 3 for the preparation of the esters3.4.

This method is illustrated in Scheme 4, Example 2. In this procedure,the phosphonic acid 1.6 is reacted with excess ethyl3-bromo-2-methylpropionate 4.7 and diisopropylethylamine indimethylformamide at ca. 80° C., as described in Anal. Chem., 1987, 59,1056, to produce the diester 4.8.

Using the above procedure, but employing, in place of ethyl3-bromo-2-methylpropionate 4.7, different haloesters 4.1, thecorresponding products 4.3 are obtained.

The diesters 4.3 are also obtained by displacement reactions ofactivated derivatives 1.7 of the phosphonic acid with the hydroxyesters4.2. The displacement reaction is performed in a polar solvent in thepresence of a suitable base, as described in Scheme 3. The displacementreaction is performed in the presence of an excess of the hydroxyester,to afford the diester product 4.3 in which the ester substituents areidentical, or sequentially with limited amounts of differenthydroxyesters, to prepare diesters 4.3 in which the ester substituentsare different.

The methods are illustrated in Scheme 4, Examples 3 and 4. As shown inExample 3, the phosphoryl dichloride 2.22 is reacted with three molarequivalents of ethyl 3-hydroxy-2-(hydroxymethyl)propionate 4.9 intetrahydrofuran containing potassium carbonate, to obtain the diesterproduct 4.10.

Using the above procedure, but employing, in place of ethyl3-hydroxy-2-(hydroxymethyl)propionate 4.9, different hydroxyesters 4.2,the corresponding products 4.3 are obtained.

Scheme 4, Example 4 depicts the displacement reaction between equimolaramounts of the phosphoryl dichloride 2.22 and ethyl2-methyl-3-hydroxypropionate 4.11, to yield the monoester product 4.12.The reaction is conducted in acetonitrile at 70° C. in the presence ofdiisopropylethylamine. The product 4.12 is then reacted, under the sameconditions, with one molar equivalent of ethyl lactate 4.13, to give thediester product 4.14.

Using the above procedures, but employing, in place of ethyl2-methyl-3-hydroxypropionate 4.11 and ethyl lactate 4.13, sequentialreactions with different hydroxyesters 4.2, the corresponding products4.3 are obtained.

2,2-Dimethyl-2-aminoethylphosphonic acid intermediates can be preparedby the route in Scheme 5. Condensation of 2-methyl-2-propanesulfinamidewith acetone give sulfinyl imine 11 (J. Org. Chem. 1999, 64, 12).Addition of dimethyl methylphosphonate lithium to 11 afford 12. Acidicmethanolysis of 12 provide amine 13. Protection of amine with Cbz groupand removal of methyl groups yield phosphonic acid 14, which can beconverted to desired 15 (Scheme 5a) using methods reported earlier on.An alternative synthesis of compound 14 is also shown in Scheme 5b.Commercially available 2-amino-2-methyl-1-propanol is converted toaziridines 16 according to literature methods (J. Org. Chem. 1992, 57,5813; Syn. Lett. 1997, 8, 893). Aziridine opening with phosphite give 17(Tetrahedron Lett. 1980, 21, 1623). Reprotection) of 17 affords 14.

Biological Activity of HIV-Integrase Inhibitor Compounds

Representative compounds of the invention were tested for biologicalactivity by methods including anti-HIV assay, measuring inhibition ofHIV-integrase strand transfer catalysis, and cytotoxicity. See: Wolfe,et al J. Virol. (1996) 70:1424-143 2; Hazuda, et al Nucleic Acids Res.(1994) 22:1121-22; Hazuda, et al J. Virol. (1997) 71:7005-7011; Hazuda,et al Drug Design and Discovery (1997) 15.17-24; and Hazuda, et alScience (2000) 287:646-650. The antiviral activity of a compound of theinvention can be determined using pharmacological models which are wellknown in the art. While many of the compounds of the present inventiondemonstrate inhibition of integration of HIV reverse-transcribed DNA,there may be other mechanisms of action whereby HIV replication orproliferation is affected. The compounds of the invention may be activevia inhibition of HIV-integrase or other enzymes associated with HIVinfection, AIDS, or ARC. Furthermore, the compounds of the invention mayhave significant activity against other viral diseases. Thus, thespecific assays embodied in Examples x-y are not meant to limit thepresent invention to a specific mechanism of action.

Pharmaceutical Formulations and Routes of Administration

The compounds of the invention may be formulated with conventionalcarriers and excipients, which will be selected in accord with ordinarypractice. Tablets will contain excipients, glidants, fillers, bindersand the like. Aqueous formulations are prepared in sterile form, andwhen intended for delivery by other than oral administration generallywill be isotonic. Formulations optionally contain excipients such asthose set forth in the “Handbook of Pharmaceutical Excipients” (1986)and include ascorbic acid and other antioxidants, chelating agents suchas EDTA, carbohydrates such as dextrin, hydroxyalkylcellulose,hydroxyalkylmethylcellulose, stearic acid and the like.

Compounds of the invention and their physiologically acceptable salts(hereafter collectively referred to as the active ingredients) may beadministered by any route appropriate to the condition to be treated,suitable routes including oral, rectal, nasal, topical (includingocular, buccal and sublingual), vaginal and parenteral (includingsubcutaneous, intramuscular, intravenous, intradermal, intrathecal andepidural). The preferred route of administration may vary with forexample the condition of the recipient.

While it is possible for the active ingredients to be administered aloneit is preferably to present them as pharmaceutical formulations. Theformulations, both for veterinary and for human use, of the presentinvention comprise at least one active ingredient, as above defined,together with one or more pharmaceutically acceptable carriers thereforand optionally other. therapeutic ingredients. The carrier(s) must be“acceptable” in the sense of being compatible with the other ingredientsof the formulation and not deleterious to the recipient thereof.

The formulations include those suitable for oral, rectal, nasal, topical(including buccal and sublingual), vaginal or parenteral (includingsubcutaneous, intramuscular, intravenous, intradermal, intrathecal andepidural) administration. The formulations may conveniently be presentedin unit dosage form and may be prepared by any of the methods well knownin the art of pharmacy. Such methods include the step of bringing intoassociation the active ingredient with the carrier which constitutes oneor more accessory ingredients. In general the formulations are preparedby uniformly and intimately bringing into association the activeingredient with liquid carriers or finely divided solid carriers orboth, and then, if necessary, shaping the product.

Formulations of the present invention suitable for oral administrationmay be presented as discrete units such as capsules, cachets or tabletseach containing a predetermined amount of the active ingredient, as apowder or granules; as solution or a suspension in an aqueous liquid ora non-aqueous liquid; or as an oil-in-water liquid emulsion or awater-in-oil liquid emulsion. The active ingredient may also bepresented as a bolus, electuary or paste.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared bycompressing in a suitable machine the active ingredient in afree-flowing form such as a powder or granules, optionally mixed with abinder, lubricant, inert diluent, preservative, surface active ordispersing agent. Molded tablets may be made by molding in a suitablemachine a mixture of the powdered compound moistened with an inertliquid diluent. The tablets may optionally be coated or scored and maybe formulated so as to provide slow or controlled release of the activeingredient therein.

For infections of the eye or other external tissues e.g. mouth and skin,the formulations are preferably applied as a topical ointment or creamcontaining the active ingredient(s) in an amount of, for example, 0.075to 20% w/w (including active ingredient(s) in a range between 0.1% and20% in increments of 0.1% w/w such as 0.6% w/w, 0.7% w/w, etc),preferably 0.2 to 15% w/w and most preferably 0.5 to 10% w/w. Whenformulated in an ointment, the active ingredients may be employed witheither a paraffinic or a water-miscible ointment base. Alternatively,the active ingredients may be formulated in a cream with an oil-in-watercream base.

If desired, the aqueous phase of the cream base may include, forexample, at least 30% w/w of a polyhydric alcohol, i.e. an alcoholhaving two or more hydroxyl groups such as propylene glycol, butane1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol(including PEG400) and mixtures thereof. The topical formulations maydesirably include a compound which enhances absorption or penetration ofthe active ingredient through the skin or other affected areas. Examplesof such dermal penetration enhancers include dimethylsulfoxide andrelated analogs.

The oily phase of the emulsions of this invention may be constitutedfrom known ingredients in a known manner. While the phase may comprisemerely an emulsifier (otherwise known as an emulgent), it desirablycomprises a mixture of at least one emulsifier with a fat or an oil orwith both a fat and an oil. Preferably, a hydrophilic emulsifier isincluded together with a lipophilic emulsifier which acts as astabilizer. It is also preferred to include both an oil and a fat.Together, the emulsifier(s) with or without stabilizer(s) make up theso-called emulsifying wax, and the wax together with the oil and fatmake up the so-called emulsifying ointment base which forms the oilydispersed phase of the cream formulations.

Emulgents and emulsion stabilizers suitable for use in the formulationof the present invention include Tween™ 60, Span™ 80, cetostearylalcohol, benzyl alcohol, myristyl alcohol, glyceryl mono-stearate andsodium lauryl sulfate.

The choice of suitable oils or fats for the formulation is based onachieving the desired cosmetic properties, since the solubility of theactive compound in most oils likely to be used in pharmaceuticalemulsion formulations is very low. Thus the cream should preferably be anon-greasy, non-staining and washable product with suitable consistencyto avoid leakage from tubes or other containers. Straight or branchedchain, mono- or dibasic alkyl esters such as di-isoadipate, isocetylstearate, propylene glycol diester of coconut fatty acids, isopropylmyristate, decyl oleate, isopropyl palmitate, butyl stearate,2-ethylhexyl palmitate or a blend of branched chain esters known asCrodamol CAP may be used, the last three being preferred esters. Thesemay be used alone or in combination depending on the propertiesrequired. Alternatively, high melting point lipids such as white softparaffin and/or liquid paraffin or other mineral oils can be used.

Formulations suitable for topical administration to the eye also includeeye drops wherein the active ingredient is dissolved or suspended in asuitable carrier, especially an aqueous solvent for the activeingredient. The active ingredient is preferably present in suchformulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10%particularly about 1.5% w/w.

Formulations suitable for topical administration in the mouth includelozenges comprising the active ingredient in a flavored basis, usuallysucrose and acacia or tragacanth; pastilles comprising the activeingredient in an inert basis such as gelatin and glycerin, or sucroseand acacia; and mouthwashes comprising the active ingredient in asuitable liquid carrier.

Formulations for rectal administration may be presented as a suppositorywith a suitable base comprising for example cocoa butter or asalicylate.

Formulations suitable for nasal administration wherein the carrier is asolid include a coarse powder having a particle size for example in therange 20 to 500 microns (including particle sizes in a range between 20and 500 microns in increments of 5 microns such as 30 microns, 35microns, etc), which is administered in the manner in which snuff istaken, i.e. by rapid inhalation through the nasal passage from acontainer of the powder held close up to the nose. Suitable formulationswherein the carrier is a liquid, for administration as for example anasal spray or as nasal drops, include aqueous or oily solutions of theactive ingredient. Formulations suitable for aerosol administration maybe prepared according to conventional methods and may be delivered withother therapeutic agents such as pentamidine for treatment ofpneumocystis pneumonia.

Formulations suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or spray formulationscontaining in addition to the active ingredient such carriers as areknown in the art to be appropriate.

Formulations suitable for parenteral administration include aqueous andnon-aqueous sterile injection solutions which may contain anti-oxidants,buffers, bacteriostats and solutes which render the formulation isotonicwith the blood of the intended recipient; and aqueous and non-aqueoussterile suspensions which may include suspending agents and thickeningagents. The formulations may be presented in unit-dose or multi-dosecontainers, for example sealed ampoules and vials, and may be stored ina freeze-dried (lyophilized) condition requiring only the addition ofthe sterile liquid carrier, for example water for injections,immediately prior to use. Extemporaneous injection solutions andsuspensions may be prepared from sterile powders, granules and tabletsof the kind previously described. Preferred unit dosage formulations arethose containing a daily dose or unit daily sub-dose, as herein aboverecited, or an appropriate fraction thereof, of an active ingredient.

It should be understood that in addition to the ingredients particularlymentioned above the formulations of this invention may include otheragents conventional in the art having regard to the type of formulationin question, for example those suitable for oral administration mayinclude flavoring agents.

The present invention further provides veterinary compositionscomprising at least one active ingredient as above defined together witha veterinary carrier therefor. Veterinary carriers are materials usefulfor the purpose of administering the composition and may he solid,liquid or gaseous materials which are otherwise inert or acceptable inthe veterinary art and are compatible with the active ingredient. Theseveterinary compositions may be administered orally, parenterally or byany other desired route.

Compounds of the invention can be used to provide controlled releasepharmaceutical formulations containing as active ingredient one or morecompounds of the invention (“controlled release formulations”) in whichthe release of the active ingredient can be controlled and regulated toallow less frequency dosing or to improve the pharmacokinetic ortoxicity profile of a given invention compound. Controlled releaseformulations adapted for oral administration in which discrete unitscomprising one or more compounds of the invention can be preparedaccording to conventional methods. Controlled release formulations maybe employed for the treatment or prophylaxis of various microbialinfections particularly human bacterial, human parasitic protozoan orhuman viral infections caused by microbial species including Plasmodium,Pneumocystis, herpes viruses (CMV, HSV 1, HSV 2, VZV, and the like),retroviruses, adenoviruses and the like. The controlled releaseformulations can be used to treat HIV infections and related conditionssuch as tuberculosis, malaria, pneumocystis pneumonia, CMV retinitis,AIDS, AIDS-related complex (ARC) and progressive generalizedlymphadeopathy (PGL), and AIDS-related neurological conditions such asmultiple sclerosis, and tropical spastic paraparesis. Other humanretroviral infections that may be treated with the controlled releaseformulations according to the invention include Human T-cellLymphotropic virus (HTLV)-I and IV and HIV-2 infections. The inventionaccordingly provides pharmaceutical formulations for use in thetreatment or prophylaxis of the above-mentioned human or veterinaryconditions and microbial infections.

Combination Therapy

The compounds of the invention may be employed in combination with othertherapeutic agents for the treatment or prophylaxis of the infections orconditions indicated above. Examples of such further therapeutic agentsinclude agents that are effective for the treatment or prophylaxis ofviral, parasitic or bacterial infections or associated conditions or fortreatment of tumors or related conditions include3′-azido-3′-deoxythymidine (zidovudine, AZT), 2′-deoxy-3′-thiacytidine(3TC), 2′,3′-dideoxy-2′,3′-didehydroadenosine (D4A),2′,3′-dideoxy-2′,3′-didehydrothymidine (D4T), carbovir (carbocyclic2′,3′-dideoxy-2′,3′-didehydroguanosine), 3′-azido-2′,3′-dideoxyuridine,5-fluorothymidine, (E)-5-(2-bromovinyl)-2′-deoxyuridine (BVDU),2-chlorodeoxyadenosine, 2-deoxycoformycin, 5-fluorouracil,5-fluorouridine, 5-fluoro-2′-deoxyuridine,5-trifluoromethyl-2′-deoxyuridine, 6-azauridine, 5-fluoroorotic acid,methotrexate, triacetyluridine,1-(2′-deoxy-2′-fluoro-1-β-arabinosyl)-5-iodocytidine (FIAC))tetrahydro-imidazo(4,5,1-jk)-(1,4)-benzodiazepin-2(1H)-thione (TIBO),2′-nor-cyclicGMP, 6-methoxypurine arabinoside (ara-M), 6-methoxypurinearabinoside 2′-O-valerate, cytosine arabinoside (ara-C),2′,3′-dideoxynucleosides such as 2′,3′-dideoxycytidine (ddC),2′,3′-dideoxyadenosine (ddA) and 2′,3′-dideoxyinosine (ddI), acyclicnucleosides such as acyclovir, penciclovir, famciclovir, ganciclovir,HPMPC, PMEA, PMEG, PMPA, PMPDAP, FPMPA, HPMPA, HPMPDAP,(2R,5R)-9→tetrahydro-5-(phosphonomethoxy)-2-furanyladenine,(2R,5R)-1→tetrahydro-5-(phosphonomethoxy)-2-furanylthymine, otherantivirals including ribavirin (adenine arabinoside),2-thio-6-azauridine, tubercidin, aurintricarboxylic acid,3-deazaneoplanocin, neoplanocin, rimantidine, adamantine, and foscarnet(trisodium phosphonoformate), antibacterial agents includingbactericidal fluoroquinolones (ciprofloxacin, pefloxacin and the like),aminoglycoside bactericidal antibiotics (streptomycin, gentamicin,amicacin and the like) β-lactamase inhibitors (cephalosporins,penicillins and the like), other antibacterials including tetracycline,isoniazid, rifampin, cefoperazone, claithromycin and azithromycin,antiparasite or antifungal agents including pentamidine(1,5-bis(4′-aminophenoxy)pentane), 9-deaza-inosine, sulfamethoxazole,sulfadiazine, quinapyramine, quinine, fluconazole, ketoconazole,itraconazole, Amphotericin B, 5-fluorocytosine, clotrimazole,hexadecylphosphocholine and nystatin, renal excretion inhibitors such asprobenicid, nucleoside transport inhibitors such as dipyridamole,dilazep and nitrobenzylthioinosine, immunomodulators such as FK506,cyclosporin A, thymosin α-1, cytokines including TNF and TGF-β,interferons including IFN-α, IFN-β, and IFN-γ, interleukins includingvarious interleukins, macrophage/granulocyte colony stimulating factorsincluding GM-CSF, G-CSF, M-CSF, cytokine antagonists including anti-TNFantibodies, anti-interleukin antibodies, soluble interleukin receptors,protein kinase C inhibitors and the like.

EXAMPLES Example 1 N-4-fluorobenzyl-succinimide 1

Freshly ground potassium carbonate, K₂CO₃ (31 g, 225 mmol) was added todry acetone (200 ml) in a 3-necked flask equipped with drying tube,condenser, and mechanical stirrer. Succinimide (7.43 g, 75 mmol) and4-fluorobenzylbromide (11.21 mL, 90 mmol) were added. The mixture wasrefluxed for 19 hours and filtered through Celite. Acetone was removedunder vacuum, diluted with EtOAc, washed with saturated aqueous sodiumbicarbonate and also with brine, dried (MgSO₄), filtered andconcentrated to give crude. Crude product was chromatographed(EtOAc/Hexane) on silica gel to give N-4-fluorobenzyl-succinimide 1 aswhite solid (13.22 g, 85%). ¹H NMR (CDCl₃) δ 7.4 (dd, 2H), 7.0 (t, 2H),4.6 (s, 1H), 2.7 (s, 4 H).

Example 2 5,8-Dihydroxy-[6,7]-N-(4-fluorobenzyl)-succinimido-quinoline 2

N-4-fluorobenzyl-succinimide 1 (8 g, 38.6 mmol) and 2,3-pyridinecarboxylic acid dimethyl ester (7.9 g, 40.6 mmol) were dissolved in drytetrahydrofuran (THF, 78 mL) and dry methanol (MeOH, 1.17 mL) in a3-necked flask with mechanical stirrer and condenser. Sodium hydride(NaH, 60% in mineral oil, 3.4 g, 85 mmol) was added slowly in fourportions. The mixture was stirred until bubbling ceased, then refluxedfor 24 hours. HCl (30 mL 6 M) was then added to the mixture while in anice bath, with stirring for 15 minutes. Diethylether (100 mL) was added.The precipitate was filtered, washed with diethylether and H₂O, anddried under vacuum at 100° C. Crude product was then recrystallized from1 L refluxing dioxane and dried under vacuum at 100° C. to give solid5,8-Dihydroxy-[6,7]-N-(4-fluorobenzyl)-succinimido-quinoline 2 (8.6 g,66%). ¹H NMR (CD₃SOCD₃) δ 9.05 (d, 1H), 8.75 (d, 1H), 7.79 (dd, 1 H),7.37 (dd, 2 H), 7.17 (t, 2H), 4.73 (s, 2 H). mp: 281.9-284.0.

Example 3 5-O-Propanoate,8-hydroxy-[6,7]-N-(4-fluorobenzyl)-succinimido-quinoline 3

5,8-Dihydroxy-[6,7]-N-(4-fluorobenzyl)-succinimido-quinoline 2 isacylated with propanoyl chloride to give 5-O-propanoate,8-hydroxy-[6,7]-N-(4-fluorobenzyl)-succinimido-quinoline 3.

Example 4 Carbonic acid ethyl ester7-(4-fluoro-benzyl)-9-hydroxy-6,8-dioxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-5-ylester 4

5,8-Dihydroxy-[6,7]-N-(4-fluorobenzyl)-succinimido-quinoline (300 mg,0.887 mmol) 2 was suspended in 1,4 dioxane (5 mL) and water (20 mL). Anaqueous solution of NaOH (0.567 M, 3.1 mL) was added slowly to form redsolution which was then cooled in an ice-water bath. Ethyl chloroformate(0.093 mL, 0.975 mmol) was added and the mixture was stirred at roomtemperature for 30 minutes. Dichloromethane and 1N aqueous HCl wereadded to the mixture in a separate. The aqueous layer was extracted withdichloromethane two more times. The combined organic solution was washedwith brine, dried (MgSO4) and concentrated. The crude product wascrystallized from EtOAc to give carbonic acid ethyl ester7-(4-fluoro-benzyl)-9-hydroxy-6,8-dioxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-5-ylester 4 (136 mg, 37%) as a yellow solid. ¹H NMR (CDCl₃) δ 9.0 (d, 1H),8.5 (d, 1H), 7.7 (dd, 1H), 7.5 (t, 2H), 7.4 (t, 2 H), 7.0 (t, 2 H), 4.8(s, 2H), 4.5 (q, 2 H), 1.5 (t, 3H); MS: 409 (M−1)

Example 5 Carbonic acid ethyl ester7-(4-fluoro-benzyl)-9-methoxymethoxy-6,8-dioxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-5-ylester 5

Carbonate (23.6 mg, 0.08 mmol) 4 was dissolved in acetonitrile (2 mL).Chloromethyl methyl ether (0.03 mL, 0.17 mmol) and Cs₂CO₃ (74 mg, 0.23mmol) were added consecutively. The mixture was stirred at roomtemperature for 30 minutes when most of the starting material wasconsumed as indicated by TLC. Dichloromethane was added and the solutionwas washed with 1N HCl and brine, dried (MgSO₄) and concentrated. Thecrude product was chromatographed on silica gel column, eluting withEtOAc/hexanes to give the product, carbonic acid ethyl ester7-(4-fluoro-benzyl)-9-methoxymethoxy-6,8-dioxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-5-ylester 5 as a white solid (18 mg, 70%). ¹H NMR (CDCl₃) δ 9.1 (dd, 1H),8.5 (dd, 1H), 7.7 (dd, 1H), 7.4 (dd, 2H), 7.0 (t, 2H), 5.9 (s, 2H), 4.8(s, 2H), 4.5 (q, 2H), 3.7 (s, 1H), 1.5 (t, 3H).

Example 67-(4-Fluoro-benzyl)-5-hydroxy-9-methoxymethoxy-pyrrolo[3,4-g]quinoline-6,8-dione6

To the ethyl carbonate methoxymethyl ether 5 (70.9 mg, 0.156 mmol) inTHF (7.6 mL) at room temperature was added a solution (5 mL) of K₂CO₃(215 mg, 1.56 mmol) in water and 4-dimethylaminopyridine (3.8 mg, 0.03mmol). The yellow solution was stirred at room temperature undernitrogen atmosphere overnight. Most of THF was removed under reducedpressure at 30-40° C. and the remaining solution was diluted withdichloromethane, washed with 1N HCl and brine, dried (MgSO₄) andconcentrated to give solid crude product (51 mg, 85%), which istriturated in diethylether/hexane to afford the product,7-(4-fluoro-benzyl)-5-hydroxy-9-methoxymethoxy-pyrrolo[3,4-g]quinoline-6,8-dione6 as a yellow solid (34 mg). ¹H NMR (CDCl₃) δ 9.1 (dd, 1H), 8.7 (dd,1H), 7.6 (dd, 1H), 7,4 (dd, 2H), 7.0 (t, 2H), 5.8 (s, 2H), 4.8 (s, 2H),3.7 (s, 1H). MS: 383 (M+1); 381 (M−1).

Example 7 Trifluoro-methanesulfonic acid7-(4-fluoro-benzyl)-9-methoxymethoxy-6,8-dioxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-5-ylester 7

To the methoxymethyl ether 6 (13.7 mg, 0.036 mmol) in dichloromethane (1mL) at −78° C. were added N,N-diisopropylethylamine (0.019 mL, 0.1 mmol)and trifluoromethanesulfonic anhydride (0.012 mL, 0.054 mmol)successively. The solution was stirred at the same temperature for 30minutes and diluted with dichloromethane, washed with water and brine,dried (MgSO₄) and concentrated. The mixture was chromatographed on asilica gel column, eluting with EtOAc/hexanes to afford the product,trifluoro-methanesulfonic acid7-(4-fluoro-benzyl)-9-methoxymethoxy-6,8-dioxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-5-ylester 7 (6 mg, 33%). ¹H NMR (CDCl₃) δ 9.1 (dd, 1H), 8.5 (dd, 1H), 7.8(dd, 1H), 7.5 (dd, 2H), 7.0 (t, 2H), 5.9 (s, 2H), 4.9 (s, 2H), 3.7 (s,1H). ¹⁹F NMR (CDCl₃) δ −72.8.

The reaction was repeated, where monophenol 6 (0.0444 g, 0.116 mmol) wasdissolved in 2 mL dry dichloromethane. To this was addeddiisopropylethylamine (0.06 mL, 0.348 mmol.) After cooling to −78° C.,triflic anhydride was added (0.029 mL, 0.342 mmol) and was stirred atthis temperature for thirty minutes. Reaction was then complete by TLC,diluted with dichloromethane, washed with 1M HCl, saturated NaHCO₃solution, dried (MgSO₄) and organics concentrated to give product,trifluoro-methanesulfonic acid7-(4-fluoro-benzyl)-9-methoxymethoxy-6,8-dioxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-5-ylester 7 (0.06 g, 0.116 mmol, 100%) which was used as crude for the nextreaction. ¹H NMR (CDCl₃) δ 9.15 (dd, 1H), 8.46 (d, 1H), 7.47 (dd, 1H),7.01 (t, 2H), 5.92 (s, 2H), 4.87 (s, 2H.), 3.67 (s, 3H); MS: 537 (M+Na).

Example 87-(4-Fluoro-benzyl)-5-methoxy-9-methoxymethoxy-pyrrolo[3,4-g]quinoline-6,8-dione8

Methoxymethyl ether 6 (0.02 g, 0.052 mmol) was dissolved in 2 mL drydichloromethane at 0° C. An excess of a diazomethane solution indiethylether was added. After about 20 minutes, all starting 6 wasconsumed. The mixture was concentrated in vacuo to give crude7-(4-fluoro-benzyl)-5-methoxy-9-methoxymethoxy-pyrrolo[3,4-g]quinoline-6,8-dione8 (0.0223 g, 0.0527 mmol). ¹H NMR (CDCl₃) δ 9.1 (dd, 1H), 8.7 (dd, 1H),7.6 (dd, 1H), 7.5 (t, 2H), 7.0 (t, 2H), 5.8 (s, 2 H), 4.8 (s, 2 H), 4.4(s, 3H), 3.7 (s, 3H). MS: 397 (M+1); 419 (M+23).

Example 97-(4-Fluoro-benzyl)-9-hydroxy-5-methoxy-pyrrolo[3,4-g]quinoline-6,8-dione9

Crude diether 8 (0.0223 g, 0.0527 mmol) was dissolved in 1 mLdichloromethane. Ten equivalents of tuifluoroacetic acid was added. Themixture was stirred at room temperature for 45 minutes. The reactionmixture was concentrated and azeotroped with toluene (2×) to give crude7-(4-fluoro-benzyl)-9-hydroxy-5-methoxy-pyrrolo[3,4-g]quinoline-6,8-dione9 which was triturated with 8 mL of 1:1 diethylether/hexane and filteredto give 9 (0.0161 g, 0.0456 mmol, 83% for two steps). ¹H NMR (CDCl₃) δ9.0 (br s, 1 H), 8.7 (d, 1 H), 7.7 (d, 1 H), 7.5 (m, 2 H), 7.0 (t, 2 H),4.8 (s, 2H), 4.4 (s, 3H). MS: 353 (M+1).

Example 105-Allyloxy-7-(4-fluoro-benzyl)-9-methoxymethoxy-pyrrolo[3,4-g]quinoline-6,8-dione10

Methoxymethyl ether 6 (0.0172 g, 0.045 mmol) was dissolved in 1.5 mL drydimethylformamide (DMF). Ground K₂CO₃(0.0186 g, 0.135 mmol) was added,followed by allyl bromide (0.0077 mL, 0.09 mmol). The mixture wasstirred at room temperature overnight, then diluted with 100 mL ofethylacetate, washed with saturated NH₄Cl solution, dried (MgSO₄), andconcentrated to give crude 10. The crude product 10 was chromatographedon silica gel, elating with ethylacetate and hexanes to give white solidallyl, methoxymethyl diether 10: (0.0063 g, 33%). ¹H NMR (CDCl₃) δ 9.1(dd, 1H), 8.8 (dd, 1H), 7.6 (dd, 1H), 7.5 (dd, 2H), 7.0 (t, 2H), 6.1 (m,1H), 5.8 (s, 2H), 5.5 (d, 1H), 5.3 (d, 1H), 5.1 (d, 2H), 4.8 (s, 2H).MS: 423 (M+1); 445 (M+23).

Example 115-Allyloxy-7-(4-fluoro-benzyl)-9-hydroxy-pyrrolo[3,4-g]quinoline-6,8-dione11

5-Allyloxy-7-(4-fluoro-benzyl)-9-methoxymethoxy-pyrrolo[3,4-g]quinoline-6,8-dione10 was dissolved in 1 mL dichloromethane. Ten equivalents oftrifluoroacetic acid was added and the mixture was stirred at roomtemperature. After one hour another 10 equivalents of trifluoroaceticacid was added. The mixture was then stirred overnight, concentrated invacuo, and azeotroped with toluene (2×), to give crude 11 which wastriturated with 2 mL of 1:1 diethylether/hexane two times to give allylether 11 (0.0025 g, 0.0066 mmol, 44%). ¹H NMR (CDCl₃) δ 9.0 (s, 1H), 8.7(d, 1H), 7.7 (m, 1H), 7.5 (m, 2H), 7.0 (t, 2H), 6.1 (m, 1H), 5.4 (d,1H), 5.3 (d, 1H), 5.1 (d, 2H), 4.8 (s, 2H). MS: 379 (M+1).

Example 127-(4-Fluoro-benzyl)-5-hydroxy-9-triisopropylsilanyloxy-pyrrolo[3,4-g]quinoline-6,8-dione12

A solution of7-(4-fluoro-benzyl)-5,9-dihydroxy-pyrrolo[3.4-g]quinoline-6,8-dione 2(1.039 g, 3.07 mmol) in 31 mL of DMF was stirred with imidazole (314 mg,4.62 mmol) and triisopropylsilylchloride (TIPSCl, 0.723 mL, 3.38 mmol)under a N₂ atmosphere for 1.5 days when most of the starting materialswas converted to the regiospecific mono TIPS (triisopropylsilyl)protected compound. The solid bisphenol left in the reaction wasfiltered and recycled. The mother liquor was dried and the residue wassuspended in EtOAc. The organic layer was washed with water and dried.The resulted solid 12 was carried to the next step. EI MS (m/z) 495.6[MH⁺], 517.4 [M+Na].

Example 137-(4-Fluoro-benzyl)-5-methoxy-9-triisopropylsilanyloxy-pyrrolo[3,4-g]quinoline-6,8-dione13

A mixture of 12 from the monosilylation reaction was heated at 40° C. inanhydrous acetonitrile with K₂CO₃ (1.64 g, 11.8 mmol) and methyl iodide(4.2 g, 29.6 mmol) for 5 hours. The reaction mixture was worked up byaddition of H₂O and EtOAc. The organic layer was washed with H₂O and thesolvent was removed in vacuo. The residue was purified by columnchromatography using a gradient of 10% EtOAc-Hex to elute the product 13as a yellow solid (72% for two steps). ¹H NMR (300 MHz, CDCl₃) δ 1.13(d, 18H, J=8 Hz), 1.53 (septet, 3H, J=7 Hz), 4.29 (s, 3H), 4.84 (s, 2H),7.00 (t, 2H, J=8 Hz), 7.48 (dd, 2H, J=5, 8 Hz), 7.58 (dd, 1H, J=4, 8Hz), 8.65 (dd, 1H, J=2, 8 Hz), 8.93 (dd, 1H, J=2, 4 Hz); EI MS (m/z)509.7 [MH⁺], 531.4 [M+Na].

Example 147-(4-Fluoro-benzyl)-6-hydroxy-5-methoxy-6-phenyl-9-triisopropylsilanyloxy-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one14

A mixture of 13 (36 mg, 0.071 mmol) in 0.35 mL of dry THF was cooled to0° C. A 26 μL aliquot of a 3 M solution of phenyl magnesium bromide inether (0.078 mmol) was added to the mixture and the reaction was allowedto warm up to room temperature. The reaction was worked up in 30 minuteswhen the reaction was complete as indicated by TLC. The mixture wasdiluted with EtOAc and washed with water. The product 14 was purified bycolumn chromatography using 20% EtOAc-Hex solvent system to provide 33mg (80%) of the product as a solid. ¹H NMR (300 MHz, CDCl₃) δ 1.20 (s,18H), 1.52-1.68 (m, 3H), 2.95 (s, 1H), 3.93 (s, 3H), 4.08 (d, 1H, J=15Hz), 4.77 (d, 1H, J=15 Hz), 6.85 (t, 2H, J=9 Hz), 7.19-7.25 (m, 2H),7.25-7.35 (m, 3H), 7.39-7.49 (m, 3H), 8.26 (d, 1H, J=8 Hz,), 8.84 (br d,1H, J=4 Hz); ¹⁹F NMR (282.6 MHz, CDCl₃) δ −76.2, 60.7; EI MS (m/z) 587.5[MH⁺], 609.4 [M+Na].

Example 157-(4-Fluoro-benzyl)-6,9-dihydroxy-5-methoxy-6-phenyl-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one15

A mixture of 14 (27 mg, 0.046 mmol) in THF (0.46 mL) and tetrabutylammonium fluoride (50 μL, 0.050 mmol) was stirred at room temperatureunder a N₂ atmosphere for 2 hours when reaction was complete asdemonstrated by LCMS analysis. The organic solvent was removed in vacuoand the residue was suspended in EtOAc. The organic layer was washedwith water and dried. The solid was washed with hexane and dried toprovide 15 mg (76%) of the product 15 as a light orange solid. ¹H NMR(300 MHz, CD₃OD) δ 3.54 (s, 3H), 4.36 (d, 1H, J=15 Hz), 4.48 (d, 1H,J=15 Hz), 6.84 (t, 2H, J=9Hz), 7.17-7.23 (m, 2H), 7.24-7.26 (m, 3H),7.35-7.46 (m, 2H), 7.62 (dd, 1H, J=4, 9 Hz), 8.44 (d, 1H, J=9 Hz), 8.89(d, 1H, J=3 Hz); ¹⁹F NMR (282.6 MHz, CDCl₃) δ 58.5; EI MS (m/z) 431.2[MH⁺], 453.2 [M+Na].

Example 167-(4-Fluoro-benzyl)-6-hydroxy-5-methoxy-6-methyl-9-triisopropylsilanyloxy-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one16

Under a nitrogen atmosphere, a solution of 13 (90 mg, 0.18 mmol) wasdissolved in 0.885 mL of dry THF. A solution of 3 M of methylmagnesiumbromide in ether (71 μL, 0.213 mmol) was added. The solution was allowedto stir at ambient temperature for 2 hours when TLC indicated completeconsumption of starting materials. The reaction mixture was diluted withEtOAc and washed with water and saturated aqueous NH₄Cl. The organiclayer was reduced in vacuo to 1 mL and cooled to get the product 16 tocrystallize from the solvent (92 mg, 99%). ¹H NMR (300 MHz, CDCl₃) δ1.16 (d, 18H, J=8 Hz), 1.55 (septet, 3H, J=8 Hz), 1.78 (s, 3H), 2.29 (s,1H), 4.04 (s, 3H), 4.72 (ABqt, 2H, J=13 Hz), 6.99 (t, 2H, J=9 Hz), 7.38(dd, 2H, J=6, 9 Hz), 7.52 (dd, 1H, J=4, 9 Hz), 8.42 (dd, 1H, J=2, 8 Hz),8.87 (dd, 1H, J=2, 4 Hz); ¹⁹F NMR (282.6 MHz, CDCl₃) δ 60.8.

Example 177-(4-Fluoro-benzyl)-9-hydroxy-5-methoxy-6-methylene-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one17

A solution of 16 (10 mg, 0.019 mmol) in 3 mL of CH₂Cl₂ and TFA (30 μL,0.389 mmol) was aged for 18 hours. Analysis of the reaction demonstratedcomplete conversion of starting materials to the product. The solventswere removed under reduced pressure. The residue was dissolved in EtOAcand precipitated with hexanes. The mother liquor was removed and thesolid residue was washed with hexanes and subsequently with Et₂O toyield the product 17 as a solid. ¹H NMR (300 MHz, CDCl₃) δ 3.97 (s, 3H),4.99 (s, 2H), 5.04 (d, 1H, J=2 Hz), 5.63 (d, 1H, J=2 Hz), 6.90 (br s,1H), 7.04 (t, 2H, J=8 Hz), 7.31 (dd, 2H, J=5, 8 Hz), 7.71 (dd, 1H, J=4,8 Hz), 8.64 (dd, 1H, J=2, 9 Hz), 9.11 (d, 1H, J=3 Hz); ¹⁹F (282.6 MHz,CDCl₃) δ 62.1; EI MS (m/z) 351.5 [MH⁺], 383.3 [M+Na].

Example 187-(4-Fluoro-benzyl)-9-hydroxy-5-methoxy-6-methyl-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one18

To a solution of 16 (52 mg, 0.099 mmol) in 1.4 mL of dry CH₂Clunder a N₂atmosphere, was added BF₃.OEt₂ (49 μL, 0.397 mmol) followed bytriethylsilane (63 μL, 0.397 mmol). The solution was allowed to stir atambient temperature for 1 day when LCMS indicated a clean conversion ofstarting materials to the desired product. The reaction was worked up byremoving the solvent and dissolving the residue in EtOAc. The organiclayer was washed with water and the solvent removed under reducedpressure. The residue was dissolved in 1 mL of EtOAc and triturated byaddition of hexanes to provide the product 18. ¹H NMR (300 MHz, CDCl₃) δ1.60 (d, 3H, J=7 Hz), 3.93 (s, 3H), 4.28 (d, 1H, J=15 Hz), 4.65 (q, 1H,J=7 Hz), 5.25 (d, 1H, J=15 Hz), 7.06 (t, 2H, J=8 Hz), 7.32 (dd, 2H, J=6,8 Hz), 7.67 (dd, 1H, J=4, 8 Hz), 8.59 (br s, 1H), 8.61 (d, 1H, J=8 Hz),9.11 (br s, 1H); ¹³C NMR (75 MHz, CDCl₃) δ 16.9, 42.8, 54.5, 61.9,113.9, 115.7, 116.0, 122.7, 126.6, 129.8, 129.9, 130.8, 132.1, 133.1,136.7, 142.4, 147.8, 148.3, 162.3 (d, J=245 Hz), 168.1; ¹⁹F NMR (282.6MHz, CDCl₃) δ 62.5; EI MS (m/z) 353.5 [MH⁺], 385.4 [M+Na].

Example 19 Isoxazole 19

The exocyclic olefin in 17 can be utilized toward a cycloadditionreaction. Under a nitrogen atmosphere, a TIPS protected analog 17a (17mg, 0.033 mmol) was suspended in 0.17 mL of dry CH₂Cl₂. To this solutionwas added 4-chlorophenylglyoxyl-O-hydroxamyl chloride (7.3 mg, 0.034mmol) and TEA (4.7 μL, 0.034 mmol). The solution was stirred at roomtemperature for 12 hours. The reaction was worked up by diluting thesolution with EtOAc and washing the organic layer with water. Theorganic layer was removed under reduced pressure. The residue wasdissolved in EtOAc and diluted with hexanes. The solution was filteredand the mother liquor was dried to provide 18 mg (100%) of the product19 as a white solid. ¹H NMR (300 MHz, CDCl₃) δ 3.31 (d, 1H, J=19 Hz),3.94 (s, 3H), 4.01 (d, 1H, J=19 Hz), 4.36 (d, 1H, J=16 Hz), 4.96 (d, 1H,J=15 Hz), 6.95 (t, 2H, J=9 Hz), 7.29 (dd, 2H, J=5, 9 Hz), 7.55 (d, 2H,J=9 Hz), 7.65 (dd, 1H, J=4, 8 Hz), 8.29 (d, 2H, J=9 Hz), 8.45 (dd, 1H,J=2, 9 Hz), 8.99 (dd, 1H, J=2, 4 Hz); ¹⁹F NMR (282.6 MHz, CDCl₃) δ 62.8;EI MS (m/z) 532.6 [MH⁺].

Example 207-(4-Fluoro-benzyl)-6,9-dihydroxy-5-methoxy-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one20

To a solution of 13 (0.699 g, 1.38 mmol) in 14 mL of a 1:1 solution ofdry MeOH:CH₂Cl₂ under a N₂ atmosphere was added sodium borohydride(NaBH₄, 156 mg, 4.13 mmol). The reaction mixture was dried after 5 hoursand the residue was loaded onto a silica column. The product was elutedwith a 10% EtOAc-Hex to provide the product 20. ¹H NMR (300 MHz, CDCl₃)δ 1.10 (d, 9H, J=8 Hz), 1.16 (d, 9H, J=7 Hz), 1.52 (septet, 3H, J=8 Hz),3.72 (d, 1H, J=11 Hz), 4.11 (s, 3H), 4.23 (d, 1H, J=15 Hz), 4.85 (d, 1H,J=15 Hz), 5.79 (d, 1H, J=11 Hz), 6.97 (t, 1H, J=9 Hz), 7.27 (dd, 2H,J=6.9 Hz), 7.43 (dd, 1H, J=4. 8 Hz), 8.43 (dd, 1H. J=2, 8 Hz), 8.81 (dd,1H, J=2, 4 Hz); ¹³C NMR (75 MHz, CDCl₃) δ 14.8. 18.2, 41.3, 61.6, 78.6,115.3, 115.6, 116.6, 122.3, 126.0, 126.8, 130.1, 130.2, 131.1, 132.8,143.1, 143.8, 148.3, 162.1 (d, J=244 Hz), 165.2; EI MS (m/z) 511.5[MH⁺], 533.4 [M+Na].

Example 217-(4-Fluoro-benzyl)-6,9-dihydroxy-5-methoxy-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one21

A solution of 20 (35 mg, 0.069 mmol) was stirred in 0.69 mL of dry THFand 75 μL of a 1 M solution of tetra-butylammonium fluoride (THF, 0.075mmol) under a N₂ atmosphere for 2 hours at ambient temperature. Thesolution was diluted with EtOAc and the organic layer was washed withwater The organic layer was removed in vacuo to leave a yellow residue.The solid was washed with hexanes and dried to give 27 mg (100%) of theproduct 21. ¹H NMR (300 MHz, CD₃OD) δ 4.13 (s, 3H), 4.46 (d, 1H, J=15Hz), 5.04 (d, 1H, J=15 Hz), 6.01 (s, 1H), 7.09 (t, 2H, J=9 Hz),7.42-7.47 (m, 2H), 7.65 (dd, 1H, J=4, 9 Hz), 8.61 (d, 1H, J=8 Hz), 8.89(d, 1H, J=3 Hz); ¹³C NMR (75 MHz, CD₃OD) δ 41.1, 79.3, 60.0, 111.6,115.0, 115.4, 122.4, 125.1, 125.9, 129.6, 130.0, 131.5, 132.9, 139.5,142.8, 148.8, 161.8 (d, J=245 Hz), 166.7; ¹⁹F NMR (282.6 MHz, CDCl₃) δ59.4; EI MS (m/z) 355.4 [MH⁺].

Example 227-(4-Fluoro-benzyl)-9-hydroxy-5,6-dimethoxy-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one22

A solution of 21 (6.7 mg, 0.019 mmol) in a 1:1 solution of CH₂Cl₂:MeOHwas stirred with TFA (3 μL, 0.038 mmol) at room temperature for 2 hourswhen complete conversion was observed by LCMS. The solution was dried invacuo and the residue was washed with hexanes to yield 7 mg of theproduct 22. EI MS (m/z) 355.4 [MH⁺].

Example 233-[7-(4-Fluoro-benzyl)-9-hydroxy-5-methoxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-6-ylsulfanyl]-propionicacid methyl ester 23

To a solution of 20 (215 mg, 0.422 mmol) in CH₂Cl₂ (4.2 mL) and TFA (98μL, 1.26 mmol) was added methyl-3-mercaptopropionate (56 μL, 0.506mmol). The solution was stirred at ambient temperature for 5 hours whenLCMS analysis indicated complete conversion of the starting materials tothe products. The solution was dried under reduced pressure andazeotroped with CH₂Cl₂ three times to provide the product 23 as a yellowsolid. ¹H NMR (300 MHz, CDCl₃) δ 2.30-2.38 (m, 4H), 3.63 (s, 3H), 4.04(s, 3H), 4.42 (d, 1H, J=15 Hz), 5.33 (d, 1H, J=15 Hz), 5.49 (s, 1H),7.05 (t, 2H, J=9 Hz), 7.38 (dd, 2H, J=5, 8 Hz), 7.59 (dd, 1H, J=4, 9Hz), 8.53 (d, 1H, J=8 Hz), 8.91-9.01 (m, 1H); ¹⁹F NMR (282.6 MHz, CDCl₃)δ 62.6; EI MS (m/z) 457.3 [MH⁺], 479.2 [M−Na].

Example 243-[7-(4-Fluoro-benzyl)-9-hydroxy-5-methoxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-6-ylsulfanyl]-propionicacid 24

A solution of 23 (150 mg, 0.329 mmol) in 3.29 mL of a 1:2:3 solution ofH₂O:MeOH:THF was stirred with LiOH. H₂O (69 mg, 1.65 mmol) for 1 hourwhen LCMS demonstrated complete conversion of starting materials toproduct. The reaction mixture was dried under reduced pressure and theresidue was suspended in water and the pH was adjusted to 11 withaqueous 1N NaOH solution. The aqueous layer was washed with EtOAc twice.The pH of the aqueous layer was then adjusted to 5 using 1N HCl and theproduct was extracted with CH₂Cl₂ under continuous extractionconditions. The organic layer was dried in vacuo to yield the product 24as an orange solid. ¹H NMR (300 MHz, CDCl₃) δ 2.1 (s, 1H), 2.25-2.45 (m,4H), 4.04 (s, 3H), 4.43 (d, 1H, J=15 Hz), 5.32 (dd, 1H, J=3, 14 Hz),5.49 (s, 1H), 7.03 (t, 2H, J=9 Hz), 7.35 (dd, 2H, J=5, 8 Hz), 7.57 (dd,1H, J=4, 8 Hz), 8.52 (dd, 1H, J=2, 8 Hz), 8.98 (dd, 1H, J=2, 5 H); ¹³CNMR (75 MHz, CD₃OD) δ 21.4, 33.6, 41.9, 61.8, 61.9, 112.3, 115.7, 116.0,123.1, 125.0, 126.5, 130.4, 130.5, 131.8, 131.8, 139.3, 142.6, 148.3,149.6, 162.4 (d, J=245 Hz), 167.2, 175.3; ¹⁹F NMR (282.6 MHz, CDCl₃) δ62.6; EI MS (m/z) 441.4 [M−H]⁻, 883.1 [2M−2H]⁻.

Example 25N,N-Diethyl-3-[7-(4-fluoro-benzyl)-9-hydroxy-5-methoxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-6-ylsulfanyl]-propionamide25

A solution of 24 (10.7 mg, 0.024 mmol) in CH₂Cl₂ (0.24 mL) was stirredwith EDC (14 mg, 0.73 mmol) and diethyl amine (10 μL, 0.097 mmol) for 1day at ambient temperature. The product 25 was purified by reverse phaseHPLC using 5-95% A. Buffer A contained CH₃CN— 1% HOAc and B containedH₂O— 1% HOAc. ¹H NMR (300 MHz, CDCl₃) δ 0.984 (t, 3H, J=6 Hz), 1.05 (t,3H, J=7 Hz), 2.23-2.45 (m, 4H), 3.04 (q, 2H, J=7 Hz), 3.29 (q, 2H, J=8Hz), 4.06 (s, 3H), 4.47 (d, 1H, J=14 Hz), 5.31 (d, 1H, J=15 Hz), 5.50(s, 1H), 7.05 (t, 2H, J=9 Hz), 7.36-7.44 (m, 2H), 7.55-7.62 (m, 1H),8.53 (d, 1H, J=9 Hz), 8.95-9.00 (m, 1H); EI MS (m/z) 520.2 [MH⁺], 1016.9[2M+Na].

Example 26({3-[7-(4-Fluoro-benzyl)-9-hydroxy-5-methoxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-6-ylsulfanyl]-propionylamino}-methyl)-phosphonicacid diethyl ester 26

To a solution of 24 (15 mg, 0.035 mmol) in 0.35 mL of CH₂Cl₂ (0.35 mL)was added diethyl(aminomethyl)phosphonate oxalate (27 mg, 0.105 mmol),EDC (20 mg, 0.105 mmol) and TEA (15 μL, 0.105 mmol). The solution wasstirred at room temperature for 1 day when the same amount of theaminomethyl phosphonate, EDC and TEA were added. The reaction wasstirred for another day when complete conversion of starting materialsto the desired product was observed by LCMS. The product 26 was purifiedby reverse phase HPLC using 5-95% A. Buffer A contained CH₃CN— 1% HOAcand buffer B was H₂O— 1% HOAc. ¹H NMR (300 MHz, CDCl₃) δ 1.33-1.40 (m,6H), 2.37-2.45 (m, 4H), 3.60-3.72 (m, 2H), 4.05 (s, 3H), 4.06-4.18 (m,4H), 4.44 (d, 1H, J=15 Hz), 5.33 (d, 1H, J=14 Hz), 5.49 (s, 1H), 6.17(br s, 1H), 6.98-7.08 (m, 2H), 7.33-7.43 (m, 2H), 7.55-7.63 (m, 1H),8.50-8.57 (br d, 1H), 8.97 (br s, 1H); ³¹P (121.4 MHz, CDCl₃) δ 22.7;¹⁹F NMR (282.6 MHz, CDCl₃) δ 62.6; EI MS (m/z) 590.4 [M−H]⁻, 614.2[M+Na].

Example 27 (tert-Butoxycarbonyl-carboxymethyl-amino)-acetic acid 27

A mixture of iminodiacetic acid (5.1 g, 38.3 mmol) and sodium hydrogencarbonate (NaHCO₃, 12.9 g, 153 mmol) were dissolved in 50 mL of water.Once the bubbling subsided, 50 mL of THF was added followed by 10.0 g(46.0 mmol) of BOC₂O. The mixture was stirred at ambient temperature for2 days when starting materials were completely consumed as detected byESI. The reaction was worked up by removing THF and washing the aqueouslayer with Et₂O twice. The pH of the aqueous layer was then adjusted to1 using conc. HCl. The product was extracted with EtOAc and solventremoved in vacuo to provide the product as a white solid. The productwas purified by crystallization from EtOAc to give 8.04 g (90%) of clearcrystals of 27. ES MS [M−H]⁻ 232.1.

Example 28 4-(4-Fluoro-benzyl)-3,5-dioxo-piperazine-1-carboxylic acidtert-butyl ester 28

A solution of 27 (547 mg, 2.35 mmol) and carbonyl diimidazole (837 mg,5.16 mmol) in 4.7 mL of dry THF under a N₂ atmosphere was refluxed for 5minutes. Once the reaction cooled down to room temperature4-fluorobenzyl amine (0.295 mL, 2.58 mmol) was added and the mixture washeated to reflux overnight. The reaction mixture was then concentratedand re-dissolved in EtOAc. The organic layer was washed with an aqueous0.5 N HCl solution and the solvent was removed in vacuo. The product waspurified by column chromatography eluting with CH₂Cl₂ to provide cleanproduct 28 as a clear oil. ¹H NMR (300 MHz, CDCl₃) δ 1.47 (s, 9H), 4.39(s, 4H), 4.92 (s, 2H), 6.99 (t, 2H, J=9 Hz), 7.40 (dd, 2H, J=5, 9 Hz);¹³C NMR (75 MHz, CDCl₃) δ 28.1, 42.0, 47.1, 82.3, 115.2, 115.5, 131.1,131.2, 132.0, 153.0, 162.7 (d, J=245 Hz), 168.0; ¹⁹F NMR (282.6 MHz,CDCl₃) δ 62.5; EI MS (m/z) 340.5 [M+Na].

Example 29 4-(4-Fluoro-benzyl)-3,5-dioxo-piperazin-1-ium;Trifluoro-Acetate 29

A solution of 28 (26 mg, 0.080 mmol) in 2 mL of CH₂Cl₂ was stirred with1 mL of TFA for 1.5 hours when TLC indicated complete conversion to theproduct. The solution was dried in vacuo to yield a white solid. Theproduct was purified by crystallization using CH₂Cl₂. ¹H NMR (300 MHz,CD₃OD) δ 4.18 (s, 4H), 4.95 (s, 2H), 5.01 (s, 2H), 7.01 (dt, 2H, J=2, 9Hz), 7.41 (ddd, 21, J=2, 5, 9 Hz); ¹⁹F NMR (282.6 MHz, CDCl₃) δ −77.5,60.0.

Example 30 Pyridine-2,3-dicarboxylic acid 2-isopropyl ester 30

A mixture of 2,3-pyridine carboxylic anhydride (100 g, 0.67 mol) in 500mL of i-PrOH was heated at reflux for 1 day according to the procedureof Ornstein, P. et. al. J. Med. Chem. (1989) 32, 4, 827. The reactionmixture was then dried in vacuo to provide the product 30 as a whitesolid. ¹H NMR (300 MHz, CD₃OD) δ 1.37 (d, 6H, J=7 Hz), 5.27 (septet, 1H,J=6 Hz), 7.63 (dd, 1H, J=5, 8 Hz), 8.34 (dd, 1H, J=1, 8 Hz), 8.71 (d,1H, J=5 Hz); EI MS (m/z) 210.0 [MH⁺].

Example 313-4-(4-Fluoro-benzyl)-3,5-dioxo-piperazine-1-carbonyl]-pyridine-2-carboxylicacid isopropyl ester 31

A solution of 29 (54 mg, 0.16 mmol), 30 (34 mg, 0.16 mmol), EDC (92 mg,0.48 mmol), dimethylaminopyridine (20 mg, 0.16 mmol), triethylamine (67μL, 0.48 mmol) in 1.6 mL of a 1:1 mixture of CH₂Cl₂:DMF was stirred for1 day at ambient temperature. The reaction mixture was directly loadedonto a silica column and the product was eluted with a gradient of 1:1Hex-EtOAc to EtOAc followed by 10% MeOH-EtOAc. The product 31 wasobtained as a clear oil. EI MS (m/z) 414.7 [MH⁺], 436.4 [M+Na].

Example 327-(4-Fluoro-benzyl)-9-hydroxy-1,7,10a-triaza-anthracene-6,8,10-trione 32

A solution of 31 (5 mg, 0.01 mmol) in 0.3 mL of dry 0.5 M NaOMe wasstirred at ambient temperature for 15 minutes when a yellow precipitateformed. The solvent was removed in vacuo and the solid was dissolved ina mixture of CH₂Cl₂— 1N HCl. The layers were separated and the aqueouslayer was washed with CH₂Cl₂. The organic solvent was removed to providean off-white solid. The product 32 was purified by trituration usingCH₂Cl₂ and hexane. ¹H NMR (300 MHz, CDCl₃) δ 5.01 (s, 2H), 5.16 (s, 2H),7.02 (dt, 2H, J=2, 9 Hz), 7.51 (ddd, 2H, J=2, 5, 9 Hz), 7.79 (dd, 1H,J=8, 5 Hz), 8.61 (dd, 1H, J=8, 2 Hz), 9.13 (dd, 1H, J=4, 2 Hz), 12.35(s, 1H); ¹³C NMR (75 MHz, CDCl₃) δ 42.4, 46.1, 107.0, 115.5, 115.8,126.7, 127.1, 130.8, 131.4, 131.5, 132.5, 143.2, 148.4, 153.7, 156.0,162.2 (d, J=249 Hz), 163.9, 164.0; EI MS (m/z) 354.6 [MH⁺].

Example 33 3-Oxo-piperazine-1-carboxylic acid tert-butyl ester 33

To a mixture of piperazine-2-one (1.037 g, 10.4 mmol) in 52 mL ofCH₂Cl₂, was added BOC₂O (2.5 g, 11.4 mmol). The reaction becamehomogeneous after 3 hours when the starting material was completelyconsumed. The reaction was diluted with CH₂Cl₂ and the organic layer waswashed with water The solvent was removed in vacuo to yield quantitativeamount of product 33 as a white solid. ¹H NMR (300 MHz, CDCl₃) δ 1.48(s, 9H), 3.35-3.44 (m, 2H), 3.64 (t, 2H, J=5 Hz), 4.10 (s, 2H), 6.41 (brs, 1H).

Example 34 4-(4-Fluoro-benzyl)-3-oxo-piperazine-1-carboxylic acidtert-butyl ester 34

To a heterogeneous solution of 33 (1.6 g, 8.1 mmol) in 16.2 mL of dryTHF under a N₂ atmosphere was added 0.211 g (8.80 mmol) of 95% NaH. Oncethe bubbling subsided, 4-fluorobenzylbromide (1.2 mL, 9.7 mmol) wasadded dropwise to the solution. After 1 hour, when the reaction wascomplete as judged by TLC, the reaction was quenched by addition ofwater and the organic layer was diluted with EtOAc. The organic layerwas washed with water and the solvent removed in vacuo. The product waspurified by column chromatography using 1:1 EtOAc-Hex solvent system toprovide 2.3 g (93%) of the product 34 as a white solid. ¹H NMR (300 MHz,CDCl₃) δ 1.47 (s, 9H), 3.24 (t, 2H, J=5 Hz), 3.60 (t, 2H, J=5 Hz), 4.16(s, 2H), 4.59 (s, 2H), 7.03 (t, 2H, J=9 Hz), 7.26 (dd, 2H, J=5.8 Hz);¹⁹F NMR (282.6 MHz, CDCl₃) δ 62.2.

Example 35 4-(4-Fluoro-benzyl)-3-oxo-piperazin-1-ium trifluoroacetatesalt 35

A solution of 34 (1.4 g, 4.5 mmol) in 6 mL of a 1:1 solution ofCH₂Cl₂:TFA was stirred at ambient temperature for 2 hours when all ofthe starting materials were consumed as judged by TLC. The reactionmixtures were dried in vacuo to yield 1.5 g of 35 as a thick oil whichwas used in the next reaction without purification.

Example 363-[4-(4-Fluoro-benzyl)-3-oxo-piperazine-1-carbonyl]-pyridine-2-carboxylicacid isopropyl ester 36

A solution of 35 (1.46 g, 4.55 mmol) was dissolved in 20 mL of a 1:1solution of CH₂Cl₂:DMF. To this solution was added 0.95 g (4.55 mmol) of30, EDC (1.74 g, 9.10 mmol) and triethylamine (1.90 mL, 13.7 mmol). Thesolution was stirred at room temperature for 4 hours when the reactionwas complete. The solution was diluted with CH₂Cl₂ and washed withwater. The organic layer was subsequently washed with aq. saturatedsolution of NH₄Cl and the solvent was removed. The yellow residue waspurified by column chromatography using EtOAc—10% MeOH gradient to yield1.8 g (100%) of the product 36 as a clear oil. EI MS (m/z) 400.5 [MH⁺],422.3 [M+Na].

Example 377-(4-Fluoro-benzyl)-9-hydroxy-6,7-dihydro-5H-1,7,10a-triaza-anthracene-8,10-dione37

To a solution of 36 (0.900 g, 2.26 mmol) in 12 mL of dry MeOH under a N₂atmosphere was added 12.5 mL of a 0.5 M sodium methoxide (NaOMe). Thesolution was stirred at ambient temperature for 2.5 hours. The reactionwas worked up by removing the solvent and dissolving the residue inCH₂Cl₂. The organic layer was washed with a saturated aqueous solutionof NH₄Cl and dried to provide 610 mg of the product 37 as a yellowsolid. ¹H NMR (300 MHz, CDCl₃) δ 3.58 (t, 2H, J=6 Hz), 4.308 (t, 2H, J=5Hz), 4.77 (s, 2H), 7.09 (t, 2H, J=8 Hz), 7.34 (t, 2H, J=8 Hz), 7.61 (dd,1H, J=5, 8 Hz), 8.73 (d, 1H, J=8 Hz), 9.12 (d, 1H, J=3 Hz), 13.00 (s,1H); ¹³C NMR (75 MHz, CDCl₃) δ 38.8, 43.9, 49.5, 111.9, 115.9, 116.2,124.7, 130.0, 130.1, 131.0, 136.4, 146.8, 147.2, 154.7, 157.3, 163.0 (d,J=245 Hz), 163.7; ¹⁹F NMR (282.6 MHz, CDCl₃) δ 63.2; EI MS (m/z) 340.5[MH⁺], 362.3 [M+Na].

Example 38 Diphenyldiazomethane 38

Benzophenone hydrazone (25 g, 122.3 mmol) and sodium sulfate (anhydrous)(26 g, 183.5 mmol) were suspended in ether (anhydrous, 400 mL). To thismixture, a potassium hydroxy (powder) saturated ethanol solution (10 mL)was added, followed by mercury oxide (66.2 g, 305.8 mmol) to form a redsolution. This solution was shaken at room temperature for 1.5 hours.The solid was filtered off. The filtrate was concentrated to a residue,which was redissolved in 200 mL of hexane and placed in a cold roomovernight. The solidified solution was evaporated to dryness, which gavediphenyldiazomethane 38 as a red solid (24.7 g, 99.7%).

Example 39

Mono carbonate 4 (8.9 g, 21.7 mmol) was dissolved in 1,2-dichloroethane(400 mL). Diphenyldiazomethane 38 (8.4 g, 43.4 mmol) was added in oneportion. The mixture was stirred at 70° C. for 3 hours. The reaction wasmonitored by TLC (EtOAc/Hexane=3/7). After completion of the reaction,the solution was cooled down to room temperature. The solvent wasevaporated. The crude product is chromatographed on a silica gel column,eluting with EtOAc/hexane to give the product 39 as a white solid (10.1g, 80%). ¹H NMR (CDCl₃): δ 9.1 (d, 1H), 8.4 (d, 1H), 8.0 (s, 1H), 7.6(dd, 1H), 7.6 (d, 4H), 7.4 (dd, 2H), 7.2-7.3 (m, 6H), 7.0 (t, 2H), 4.8(s, 2H), 4.4 (q, 2H), 1.4 (t, 3H). MS: 577 (M+23).

The reaction was repeated, where mono-carbonate 4 (2 g, 0.4878 mmol) wasdissolved in 9 mL of dichloroethane. To this was addeddiphenyldiazomethane (0.189 g, 0.9756 mmol) and stirred at 70° C. fortwo hours. After starting material consumed, concentrated off somesolvent, and chromatographed (25% ethylacetate/hexanes) to give product39 (0.2653 g, 0.4598 mmol, 94%.) ¹H NMR (CDCl₃) δ 9.14 (d, 1H), 8.47 (d,1H), 7.99 (s, 1H), 7.61 (m, 5H), 7.43 (dd, 2H), 7.27 (m, 6H), 7.02 (dd,2H), 4.82 (s, 2H), 4.45 (q, 2H), 1.47 (t, 3H) MS: 577 (M+1)

Example 40

A solution of K₂CO₃ (24.2 g, 175.2 mmol) in water (120 mL) and4-dimethylaminopyridine (4.24 g, 35.0 mmol) was added to the ethylcarbonate 39 (10.1 g, 17.5 mmol) in THF (180 mL). The mixture is stirredat room temperature under nitrogen atmosphere overnight. Most of THF isremoved under reduced pressure at 30-40° C. and the remaining solutionis diluted with dichloromethane. To this, it is acidified with 1N HCl topH about 4. The organic phase was separated and washed with brine, dried(MgSO₄) and concentrated to give a yellow solid crude product 40 (9.9 g,100%). ¹H NMR (CDCl₃): δ 9.1 (d, 1H), 8.6 (d, 1H), 8.4 (s, 1H, (OH)),7.8 (s, 1H), 7.6 (dd, 1H), 7.6 (dd, 4H), 7.4 (d, 2H), 7.2-7.3 (m, 6H),7.0 (t, 2H), 4.8 (s, 2H). LC/MS: 527 (M+23).

Example 41

2-(Trimethylsilyl) ethanol (2.4 mL, 16.7 mmol), triphenylphosphine (3.5g, 13.4 mmol) and diethyl azodicarboxylate (92.1 mL, 13.4 mmol) wasadded to the phenol 40 (3.37 g, 6.7 mmol) in anhydrous THF (70 mL). Thesolution was stirred at room temperature for 3 hours under nitrogen. TLCindicated the completion of the reaction. The solvent was evaporated andthe residue oil was purified by silica gel chromatography, eluting withEtOAc/hexane to afford the product 41 (3.3 g, 82%). ¹H NMR (CDCl₃): δ9.1 (d, 1H), 8.6 (d, 1H), 7.9 (s, 1H), 7.6 (dd, 1H), 7.6 (d, 4H), 7.4(d, 2H), 7.2-7.3 (m, 6H), 7.0 (t, 2H), 4.8 (s, 2H), 4.6 (t, 2H), 1.2 (t,2H). MS: 605 (M+1), 627 (M+23).

Example 42

Compound 41 (3.3 g, 5.46 mmol) was dissolved in the mixture of THF (40mL), isopropanol (20 mL) and water (10 mL) and chilled to 0° C. in anice-bath. To this was added lithium borohydride (373.0 mg, 16.4 mmol)slowly. The mixture was stirred at 0° C. for 1 hour and at roomtemperature for 1 hour under nitrogen. TLC indicated the completion ofthe reaction. A solution of 1N HCl (30 mL) was added and the mixture wasextracted twice with CH₂Cl₂ (2×50 mL). The organic layer was washed withsaturated NaHCO₃ and dried over Mg₂SO₄ and evaporated to dryness to give42 as an oil (3.3 g).

Example 43

Crude product 42 was dissolved in anhydrous dichloromethane (50 mL).N-dimethylaminopyridine (66.7 mg, 0.546 mmol), N,N-diisopropylethylamine(2.85 mL, 16.4 mmol) and acetic anhydride (1.03 mL, 109 mmol) wereadded. The mixture was stirred at room temperature under nitrogenovernight. TLC indicated the completion of the reaction. The reactionwas quenched with 1N HCl (30 mL) and extracted with CH₂Cl₂ twice (2×50mL). The organic layer was washed with saturated NaHCO₃, dried (Mg₂SO₄)and concentrated to give crude product 43 (3.5 g).

Example 44

Crude product 43 was dissolved in anhydrous dichloromethane (60 mL)under nitrogen. To this solution was added 2,6-lutidine (3.2 mL, 23.7mmol), triethylsilane (10 mL), then trimethylsilyl triflate (1.5 mL, 8.2mmol) slowly. The mixture was stirred at room temperature for 3 hours.TLC indicated the completion of the reaction. It was quenched with 1NHCl (30 mL) and extracted with CH₂Cl₂ twice (2×50 mL). The organic layerwas washed with saturated NaHCO₃, dried (Mg₂SO₄) and concentrated. Theresidue was chromatographed on a silica gel column, eluting withEtOAc/Hexane to afford 44 (1.4 g, 43.4% in 3 steps from 41). ¹H NMR(CDCl₃): δ 9.0 (d, 1H), 8.4 (d, 1H), 8.0 (s, 1H), 7.7 (d, 4H), 7.4 (dd,1H), 7.1-7.3 (m, 8H), 7.0 (t, 2H), 4.8 (s, 2H), 4.2 (s, 2H), 4.1 (t,2H), 1.1 (t, 2H), 0.1 (s, 9H). MS: 591 (M+1).

Example 45

To9-benzhydryloxy-7-(4-fluoro-benzyl)-5-(2-trimethylsilanyl-ethoxy)-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one44 (300.8 mg, 0.509 mmol) in anhydrous THF (20 mL), was addedtetrabutylammonium fluoride hydrate (500 mg, 1.02 mmol). The reactionmixture turned to red and was stirred at room temperature under nitrogenfor 1 hour. The reaction was monitored by TLC (EtOAc/Hexane=3/7). Aftercompletion of the reaction, it was diluted with EtOAc (50 mL) and washedwith 1N HCl, saturated NaHCO₃ and brine. The organic layer was dried(MgSO₄) and concentrated to give a crude product 45 (280 mg).

The reaction was repeated whereby, to a solution of lactam 44 (0.026 g,0.044 mmol) in THF (0.441 mL) was added triethylamine (0.025 mL, 0.176mmol) and tetrabutylammonium fluoride in 1M THF (0.066 mL). The reactionmixture was stirred at room temperature under an inert atmosphere for 30minutes, monitored to completion by MS. The mixture was diluted withdichloromethane, washed with saturated NH₄Cl, dried (MgSO₄), andconcentrated in vacuo. The crude material 45 was taken forwardimmediately with no further purification or characterization: MS: 491(M+1).

Alternatively, to a solution of9-benzhydryloxy-7-(4-fluoro-benzyl)-5-(2-trimethylsilanyl-ethoxy)-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one44 (30 mg, 0.051 mmol) dissolved in THF (1 mL) was addedtetrabutylammonium fluoride hydrate (1M in THF, 150 μL). The reactionmixture turned to red and was stirred at room temperature for ½ hoursunder an inert atmosphere, which generated9-benzhydryloxy-7-(4-fluoro-benzyl)-5-hydroxy-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one45. TLC was used to monitor the reaction.

Example 46

Crude compound 45 was dissolved in dichloromethane (20 mL). To this wasadded cesium carbonate (200 mg, 0.611 mmol) and N-phenyltrifluoromethanesulfonimide (220 mg, 0.611 mmol). The mixture was stirred at roomtemperature under nitrogen for 16 hours. The reaction was monitored byTLC (EtOAc/Hexane=3/7). After completion of the reaction, it was dilutedwith EtOAc (50 mL) and washed with 1N HCl, saturated NaHCO₃ and brine.The organic layer was dried (MgSO₄) and concentrated. The residue waschromatographed on a silica gel column, eluting with EtOAc/Hexane toafford the clean product 46 (135 mg, 42.6% in 2 steps). ¹H NMR (CDCl₃):δ 9.1 (d, 1H), 8.3 (d, 1H), 8.0 (s, 1H), 7.7 (d, 4H), 7.6 (dd, 1H),7.2-7.4 (m, 8H), 7.1 (t, 2H), 4.8 (s, 2H), 4.4 (s, 2H), MS: 623 (M+1),645(M+23).

Example 47

To the triflate 46 (66.6 mg, 0.107 mmol) in toluene (2.8 mL)/ethanol(1.2 mL)/water (0.8 mL) was added potassium carbonate (37 mg, 0.268mmol), trans-phenylvinylboronic acid (24.5 mg, 0.160 mmol) andtetrakis(triphenylphosphine)-palladium (0) (18.5 mg, 0.016 mmol). Themixture in the flask was flushed with argon three times and heated to120° C. under argon for 3 hours. The mixture was cooled to roomtemperature, diluted with EtOAc and washed with 1N HCl, saturated NaHCO₃and brine. The organic phase was dried (MgSO₄) and concentrated. Theresidue was chromatographed on a silica gel column, eluting withEtOAc/Hexane to afford the product 47 (51.4 mg, 83%). ¹H NMR (CDCl₃): δ9.0 (d, 1H), 8.4 (d, 1H), 8.1 (s, 1H), 7.7 (d, 4H), 7.2-7.5 (m, 14H),7.1 (d, 1H), 7.0 (dd, 2H), 6.8 (d, 1H), 4.8 (s, 2H), 4.4(s, 2H). MS: 577(M+1), 599 (M+23).

Example 48

The compound 47 (12 mg, 0.02 mmol) was dissolved in dichloromethane (1mL) at room temperature under nitrogen. Triethylsilane (200 μL) wasadded followed by TFA (100 μL) slowly. The mixture became smoke anddark. It was stirred at room temperature for 30 min. The solvent wasremoved under reduced pressure. The crude product was triturated indiethylether/hexane to afford a yellow solid 48 (9 mg, 90%). ¹H NMR(CDCl₃): δ 9.0 (d, 1H), 8.6 (d, 1H), 7.5 (m, 3H), 7.2-7.4 (m, 6H), 7.1(m, 2H), 6.8 (d, 1H), 4.8 (s, 2H), 4.5 (s, 2H). MS: 411 (M+1).

Example 49

Compound 47 (405 mg, 0.7 mmol) in dichloromethane (150 mL) was chilledto −78° C. Ozone (O₃) was passed slowly into the solution over 30 min.TLC indicated the completion of the reaction. Nitrogen was bubbled intothe mixture for 10 min to expel excess O₃. Dimethyl sulfate (10 mL) wasthen added the mixture at −78° C. and the mixture was warmed to roomtemperature slowly with stirring. After 16 hours, the mixture wasevaporated to dryness and the residue was purified by chromatography ona silica gel column, eluting with methanol/dichloromethane to giveproduct of 49 (166.5 mg) and its hydrate form (122 mg), total yield of80.8%. ¹H NMR (CDCl₃): δ 10.7 (s, 1H, CHO), 9.1 (m, 2H), 8.4 (s, 1H),7.7 (d, 4H), 7.6 (dd, 2H), 7.2-7.4 (m, 8H), 7.0 (t, 2H), 4.6 (s, 2H).MS: 503 (M+1), 525 (M+23).

Example 50

The aldehyde 49 (23 g, 0.046 mmol) was dissolved in anhydrous THE (1 mL)and MeOH (0.1 mL) at room temperature. To this was added sodiumborohydride (5.2 mg, 0.14 mmol) slowly. The mixture was stirred at roomtemperature for 30 min under nitrogen. TLC indicated the completion ofthe reaction. The mixture was diluted with water (5 mL). The insolublematerial was collected by filtration and washed with hexane andair-dried to give product 50 (13.5 mg, 59%). ¹H NMR (CD₃OD): δ 9.3 (d,1H), 9.1 (4, 1H), 8.1 (dd, 1H), 8.0 (s, 1H), 7.5 (d, 4H), 7.4 (dd, 2H),7.3 (m, 6H), 7.1 (t, 2H), 5.0 (s, 2H), 4.9 (s, 2H), 4.7 (s, 2H). MS: 505(M+1), 527(M+23).

Example 51

The aldehyde 49 (121 mg, 0.24 mmol) was dissolved in anhydrous THF (5mL) and MeOH (0.5 mL) at room temperature. To this was added sodiumborohydride (27 mg, 0.72 mmol) slowly. The mixture was stirred at roomtemperature for 30 min under nitrogen. It was diluted with 1N HCl (10mL), and stirred for 10 min. The phases were separated and the aqueousphase was lyophilized to give a yellow solid, which was washed withwater and ether. The solid was dried to give 50 mg of product 51. ¹H NMR(DMSO-d₆): δ 9.0 (d, 1H), 8.8 (d, 1H), 7.5 (m, 1H), 7.4 (m, 2H), 7.2 (m,2H), 5.0 (s, 1H, PhOH), 4.8 (s, 2H), 4.7 (s, 2H), 4.5 (s, 2H). MS: 339(M+1).

The organic phase was concentrated. The residue was dissolved in DMF (2mL) 1 and purified by Prep-HPLC to give 10 mg of product 52. HPLCcondition: mobile phase A (1% AcOH in water), mobile phase B (1% AcOH inAcCN); gradient: 20% to 50% B in 30 min; flow rate: 20 mL/min; column:Phenomenex, Luna 5μ, C18 (2), 150 mm×21.2 mm. ¹H NMR (DMSO-d₆): δ 9.5(d, 1H), 89.0 (d, 1H), 7.7 (m, 1H), 7.3 (m, 2H), 7.2 (m, 2H), 4.7 (s,2H), 4.6 (s, 2H), 4.5 (s, 2H), 3.5 (s, 3H, under water peak). MS: 353(M+1).

Example 52

The aldehyde 49 (118 mg, 0.23 mmol) was dissolved in anhydrous THF (5mL) and MeOH (0.5 mL) at room temperature. To this was added sodiumborohydride (27 mg, 0.72 mmol) slowly. The mixture was stirred at roomtemperature for 30 min under nitrogen. It was diluted with 1N HCl (10mL), and stirred for 10 min. The phases were separated and the aqueousphase was lyophilized to give a yellow solid as product 51.

The alcohol 51 (crude from reduction) was suspended in dichloromethane(10 mL) at room temperature under nitrogen. Triethylsilane (3 mL) wasadded followed by TFA (1 mL) slowly. The mixture became homogeneous andwas stirred at room temperature overnight under nitrogen. The solventwas removed under reduced pressure. The crude product was dissolved in 2mL of DMF then purified by prep-HPLC to gave a clean product of 53 (22.4mg, 30%). HPLC condition: mobile phase A (1% TFA in water), mobile phaseB (1% TFA in AcCN); gradient-5% to 100% B in 20 min; flow rate: 20mL/min; column: Phenomenex, Luna 5μ, C18 (2), 150 mm×21.2 mm. ¹H NMR(CD₃OD): δ 9.0 (d, 1H), 8.9 (d, 1H), 7.9 (dd, 1H), 7.4 (d, 4H), 7.1 (t,2H), 4.8 (s, 2H), 4.9 (s, 2H), 4.5 (s, 2H), 2.5 (s, 3H). MS: 323 (M+1).

Example 53

To the compound 44 (350.0 mg, 0.592 mmol) in anhydrous THF (20 mL), wasadded tetrabutylammonium fluoride (1M in THF, 651 μl, 0.651 mmol) andtriethylamine (330 μl, 2.37 mmol). The reaction mixture turned to redand was stirred at room temperature under nitrogen for 1 hour. Thereaction forming 45 was monitored by TLC (EtOAc/Hexane=3/7).

Example 54

Triethylamine (330 μL, 2.37 mmol) was added to the reaction mixturefollowed by a catalytic amount of DMAP, and N,N-dimethylsulfamoylchloride (160 μL, 1.5 mmol). The mixture was stirred at room temperatureunder nitrogen for 16 hours. After completion of the reaction, it wasdiluted with dichloromethane (50 mL) and washed with 1N HCl, saturatedNaHCO₃ and brine. The organic layer was dried (MgSO₄) and concentrated.The residue was chromatographed on a silica gel column, eluting withEtOAc/Hexane to afford the product 54 (205.4 mg, 58% in 2 steps). ¹H NMR(CDCl₃): δ 9.0 (d, 1H), 8.4 (d, 1H), 8.0 (s, 1H), 7.7 (d, 4H), 7.5 (dd,1H), 7.1-7.3 (m, 8H), 7.0 (t, 2H), 4.8 (s, 2H), 4.4 (s, 2H), 3.0 (s,3H). MS: 598 (M+1).

Example 55

The compound 54 ((205.4 mg, 0.344 mmol) was dissolved in dichloromethane(6 mL) at room temperature under nitrogen. Triethylsilane (2 mL) wasadded followed by TFA (1 mL) slowly. The mixture became smoky and darkand was stirred at room temperature for 30 min. The solvent was removedunder reduced pressure. The crude product was triturated indiethylether/hexane to afford a yellow solid 55, 169 mg, 93%. ¹H NMR(CD₃OD): δ 9.0 (d, 1H), 8.6 (d, 1H), 7.8 (dd, 1H), 7.4 (m, 2H), 7.1 (m,2H), 4.8 (s, 2H), 4.6 (s, 2H), 3.1 (s, 6H). MS: 432 (M+1).

Example 56

The phenol 40 (1.0 g, 1.984 mmol) and DIEA (1.04 mL, 6.0 mmol) indichloromethane (20 mL) was chilled to −78° C. To this was addedtrifluoromethanesulfonic anhydride (0.78 mL, 3.0 mmol) slowly under thenitrogen. The reaction was completed in 1 hour. It was quenched with 1.5mL of methanol and stirred for 5 min more. Warmed to room temperature,it was washed with 1N HCl, saturated NaHCO₃ and brine. The organic phasewas dried (MgSO₄) and concentrated to afford the forming product 56 (1.2g, 95%).

The reaction was repeated, where monophenol 40 (0.1807 g, 0.358 mmol)was dissolved in 4 mL dry dichloromethane. To this was addeddiisopropylethylamine (0.182 mL, 1.074 mmol.) After cooling to −78° C.,triflic anhydride was added (0.14 mL, 0.537 mmol) and was stirred atthis temperature for twenty minutes. Reaction was then complete by TLC,diluted with dichloromethane, washed with 1M HCl, saturated NaHCO₃solution, dried (MgSO₄) and organics concentrated to give product(0.2518 g, 0.396 mmol, 100%) which was stored crude as a solution in 10mL dry benzene. ¹H NMR (CDCl₃) δ 9.2 (dd, 1H), 8.46 (d, 1H), 8.068 (s,1H), 7.75 (dd, 1H), 7.6 (d, 4H), 7.47 (dd, 1H), 7.27 (m, 7H), 7.19, dd,2H), 4.87 (s, 2H.) MS: 637 (M+1)

Example 57

To the triflate 56 (78.0 mg, 0.122 mmol) in toluene (2.8 mL)/ethanol(1.2 mL)/water (0.8 mL) was added potassium carbonate (42 mg, 0.306mmol), 1-octeneboronic acid (29.0 mg, 0.184 mmol) and tetrakis(triphenylphosphine)-palladium (0) (21.0 mg, 0.018 mmol). The mixture inthe flask was flushed with argon three times. It was heated to 120° C.under argon for 3 hours. Cooling to room temperature, it was dilutedwith EtOAc and washed with 1N HCl, saturated NaHCO₃ and brine. Theorganic phase was dried (MgSO₄) and concentrated. The residue waschromatographed on a silica gel column, eluting with EtOAc/Hexane toafford the product 57 (11.4 mg, 15.6%).

Example 58

The compound 57 (6 mg, 0.01 mmol) was dissolved in dichloromethane (1mL) at room temperature under nitrogen. Triethylsilane (200 μL) wasadded followed by TFA (100 μL) slowly. The mixture became smoky and darkand was stirred at room temperature for 30 min. The solvent was removedunder reduced pressure. The crude product was triturated indiethylether/hexane to afford a yellow solid TFA salt of 58, 3 mg, 57%.¹H NMR (CD₃OD): δ 9.0 (d, 1H), 8.8 (d, 1H), 7.8 (dd, 1H), 7.4 (dd, 2H),7.1 (d, 1H), 7.0 (dd, 2H), 6.2 (m, 1H), 4.8 (s, 2H), 2.4 (m, 2H), 1.6(m, 2H), 1.3-1.5 (m, 6H), 0.9 (t, 3H). MS: 433 (M+1).

Example 59

To the triflate 56 (100 mg, 0.157 mmol) in toluene (2.8 mL)/ethanol (1.2mL)/water (0.8 mL) was added potassium carbonate (54 mg, 0.392 mmol),vinylboronic acid (17 mg, 0.235 mmol) and tetrakis(triphenylphosphine)-palladium (0) (27.0 mg, 0.023 mmol). The mixture inthe flask was flushed with argon three times. It was heated to 120° C.under argon for 3 hours. Cooling to room temperature, it was dilutedwith EtOAc and washed with 1N HCl, saturated NaHCO₃ and brine. Theorganic phase was dried (MgSO₄) and concentrated. The residue waschromatographed on a silica gel column, eluting with EtOAc/Hexane toafford the product 59 (32.3 mg, 40%).

Example 60

The compound 59 (11 mg, 0.01 mmol) was dissolved in dichloromethane (1mL) at room temperature under nitrogen. Triethylsilane (200 μL) wasadded followed by TFA (100 μL) slowly. The mixture became smoky and darkand was stirred at room temperature for 30 min. The solvent was removedunder reduced pressure. The crude product was triturated indiethylether/hexane to afford a yellow solid TFA salt of 60, 2.3 mg,31.4%. ¹H NMR (CDCl₃): δ 9.0 (d, 1H), 8.8 (d, 1H), 7.7 (dd, 1H), 7.5 (m,2H), 7.0 (m, 2H), 6.0 (d, 1H), 5.6 (d, 1H), 5.3 (s, 1H, OH), 4.8 (s,2H). MS: 349 (M+1).

Example 61

The compound 59 (157 g, 0.11 mmol) was dissolved in anhydrous THF (5 mL)and MeOH (0.5 mL) at room temperature. To this was added sodiumborohydride (13 mg, 0.33 mmol) slowly. The mixture was stirred at roomtemperature for 1 hour under nitrogen. It was diluted with EtOAc (50mL), and washed with 1N HCl, saturated NaHCO₃ and brine. The organicphase was dried (MgSO₄) and concentrated. The residue was purified bysilica gel prep-TLC, eluting with EtOAc/Hexane (3/7) to afford theproduct 61 (12.5 mg, 22%).

Example 62

The compound 61 (11 mg, 0.01 mmol) was dissolved in dichoromethane (1mL) at room temperature under nitrogen. Triethylsilane (200 μL) wasadded followed by TFA (100 μL) slowly. The mixture became smoky and darkand was stirred at room temperature for 30 min. The solvent was removedunder reduced pressure. The crude product was triturated indiethylether/hexane to afford a yellow solid TFA salt of 62, 8 mg, 75%.¹H NMR (CDCl₃): δ 9.0 (d, 1H), 8.5 (d, 1H), 7.7 (dd, 1H), 7.5 (dd, 2H),7.0 (m, 2H), 4.8 (s, 2H), 3.5 (q, 2H), 1.3 (t, 3H). MS: 451 (M+1).

Example 63

Mono-phenol 6 (0.02 g, 0.052 mmol) was added to 1.5 mL drydimethylformamide. To this was added benzyl bromide (0.0124 ml, 0.104mmol) and K₂CO₃ (0.0215 g, 0.156 mmol) and stirred at 50° C. After 1.5hrs reaction completed by TLC. Diluted with 100 mL ethylacetate, washedwith saturated NH₄Cl solution and brine. The organic phase was dried(MgSO₄), concentrated, and chromatographed (25% ethylacetate/hexanes) togive product 63 (0.013 g, 0.0275 mmol, 53%.). ¹H NMR (CDCl₃) δ 9.03 (dd,1H), 8.6 (d, 1H), 7.54 (m, 6H), 7.4 (m, 2H), 7.05 (dd, 2H), 5.8 (s, 2H),5.6 (s, 2H), 4.9 (s, 2H), 3.7 (s, 3H). MS: 473 (M+1)

Example 64

Benzyl ether (0.013 g, 0.0275 mmol) was dissolved in 1 mL drydichloromethane. To this was added trifluoroacetic acid (0.0213 mL,0.275 mmol) and stirred 2.5 hrs. Concentrated off volatiles, azeotropedwith toluene (2×), concentrated to give crude product. Triturated with1:1 diethylether/hexanes to give product 64 (0.0078 g, 0.0182 mmol,66%). ¹H NMR (CDCl₃) δ 8.96 (dd, 1H), 8.6 (d, 1H), 7.6 (dd, 1H), 7.5 (m,5H), 7.37 (m, 2H), 7.05 (dd, 2H), 5.6 (s, 2H), 4.88 (s, 2H). MS: 429(M+1), 427 (M−1)

Example 65

Monophenol 6 (0.04 g, 0.1047 mmol) was dissolved in 2 mL of drydimethylformamide. To this was added 2-bromomethyl pyridine HBr salt(0.0529 g, 0.209 mmol) and K₂CO₃ (0.144 g, 1.047 mmol.) Stirred at 50°C. for twelve hours. Diluted with ethylacetate, washed with brine(saturated NaCl) and 1M HCl, dried (MgSO₄,), and concentrated. The crudeproduct was chromatographed (20 to 50% ethylacetate/hexanes) to giveproduct 65: (0.0032 g, 0.0067 mmol, 6.5%.) ¹H NMR (CDCl₃) δ 9.03 (d,1H), 8.72 (d, 1H), 8.6 (d, 1H), 7.8 (dd, 1H), 7.7 (dd, 1H), 7.57 (dd,1H), 7.48 (dd, 2H), 7.0 (dd, 2H), 5.8 (s, 2H), 5.65 (s, 2H), 4.86 (s,2H), 3.72 (s, 3H.) MS: 488 (M+1)

Example 66

Pyridyl ether 65 (0.0032 g, 0.0067 mmol) was dissolved in 1 mL drydichloromethane. To this was added trifluoroacetic acid (0.0052 mL,0.0676 mmol) and stirred 12 hrs. Concentrated off volatiles, azeotropedwith toluene (2×), concentrated to give crude product. Triturated with1:1 diethylether/hexanes to give product 66 (0.0012 g, 0.0028 mmol,42%.) ¹H NMR (CDCl₃) δ 8.96 (d, 1H), 8.73 (d, 1H), 8.6 (d, 1H), 7.8 (dd,1H), 7.7 (d, 1H), 7.63 (dd, 1H), 7.5 (dd, 2H), 7.3 (m, 1H) 7.04 (dd,2H), 5.67 (s, 2H), 4.87 (s, 2H.) MS: 430 (M+1), 428 (M−1)

Example 67

Triflate 46 in benzene was concentrated to give (0.0225 g, 0.0353 mmol)and dissolved in 3 mL of dichloroethane. To this was added triethylamine(0.0073 mL, 0.0529 mmol) and morpholine (0.0092 ml, 0.118 mmol) andreaction stirred at 65° C. After 15 hrs, reaction still incomplete byTLC, added another 0.118 mL of morpholine. After 21 hrs reaction timeconcentrated off volatiles and chromatographed (10 to 25%ethylacetate/hexanes) to give product 67 (0.0061 g, 0.01, 30%). ¹H NMR(CDCl₃) δ 9.09 (dd, 1H), 8.89 (d, 1H), 8.03 (s, 1H), 7.65 (m, 5H), 7.49(dd, 1H), 7.27 (m, 7H), 7.06 (dd, 2H), 4.85 (s, 2H), 3.92 (dd, 4H), 3.92(br m, 4H). MS: 574 (M+1)

Example 68

Tertiary amine 67 was dissolved in 0.5 mL of dichloromethane. To thiswas added 0.2 mL of triethylsilane and 0.1 mL of trifluoroacetic acid.Stirred at room temperature and after ten minutes complete by TLC.Concentrated off volatiles, azeotroped with toluene, solidified withhexane and concentrated to give crude. Triturated with 1:1diethylether/hexanes to give product 68 (0.002 g, 0.0049 mmol, 49%). ¹HNMR (CDCl₃) δ 8.98 (m, 2H), 7.7 (dd, 1H), 7.53 (dd, 2H), 7.05 (dd, 2H),4.86 (s, 2H), 3.96 (dd, 4H), 3.35 (br m, 4H). MS: 408 (M+1), 406 (M−1)

Example 69

Triflate 46 in benzene was concentrated to give (0.045 g, 0.0706 mmol)and dissolved in 3 mL of dichloroethane. To this was added triethylamine(0.0147 mL, 0.1059 mmol) and morpholine (0.0209 ml, 0.2118 mmol) andreaction stirred at 70° C. After 15 hrs of stirring, concentrated offvolatiles and chromatographed (8 to 10% ethylacetate/hexanes) to giveproduct 69 (0.0085 g, 0.01488, 44%.) ¹H NMR (CDCl₃) δ 9.068 (dd, 1H),8.79 (d, 1H), 7.8 (s, 1H), 7.6 (d, 4H), 7.57 (dd, 1H), 7.46 (dd, 2H),7.27 (m, 6H), 7.06 (dd, 2H), 4.84 (s, 2H), 3.24 (br s, 4H), 1.73 (br s,6H.) MS: 572 (M+1)

Example 70

Tertiary amine 69 was dissolved in 0.5 mL of dichloromethane. To thiswas added 0.2 mL of triethylsilane and 0.1 mL of trifluoroacetic acid.Stirred at room temperature and after ten minutes complete by TLC.Concentrated off volatiles, azeotroped with toluene, solidified withhexane and concentrated to give crude. Triturated with 1:1diethylether/hexanes to give product 70 (0.0043 g, 0.0106 mmol, 72%,) ¹HNMR (CDCl₃) δ 8.96 (dd, 1H), 8.85 (d, 1H), 7.66 (dd, 1H), 7.5 (m, 2H),7.04 (dd, 2H), 4.85 (s, 2H), 3.29 (br s, 4H), 1.77 (br s, 6H.) MS: 406(M+1), 404 (M−1)

Example 71

Monophenol 45 (0.03 g, 0.0595 mmol) was dissolved in 2 mL drydimethylformamide. To this was added ethyl bromoacetate (0.0131 mL,0.119 mmol) and freshly ground K₂CO₃ (0.025 g, 0.178 mmol.) Stirred at50° C., for two hours until starting material consumed. Concentrated offsome solvent, diluted with ethylacetate, washed with saturated NH₄Clsolution, concentrated organics to give crude product. Chromatographed(10 to 25% ethylacetate/hexanes) to give product 71 (0.0321 g, 0.054mmol, 91%.) ¹H NMR (CDCl₃) δ 9.1 (dd, 1 H), 8.96 (d, 1H), 7.9 (s, 1H),7.62 (d, 4H), 7.445 (m, 2H), 7.27 (m, 7 H), 7.059 (dd, 2H), 5.21 (s,2H), 4.83 (s, 2H), 4.22 (q, 2H), 1.23 (t, 3H). MS: 591 (M+1).

Example 72

Ethyl ester 71 was dissolved in 0.5 mL of dichloromethane. To this wasadded 0.2 mL of triethylsilane and 0.1 mL of trifluoroacetic acid.Stirred at room temperature and after ten minutes complete by TLC.Concentrated off volatiles, azeotroped with toluene to give crude.Triturated with 1:1 diethylether/hexanes to give product 72 (0.0209 g,0.049 mmol, 91%.) ¹H NMR (CDCl₃) δ 9.0 (m, 2H), 7.7 (dd, 1H), 7.5 (dd,2H), 7.04 (dd, 2H), 5.33 (s, 2H), 4.84 (s, 2H), 4.24 (q, 2H), 1.28 (t,3H.) MS: 425 (M+1), 423 (M−1)

Example 73

Monophenol 45 (0.03 g, 0.0595 mmol) was dissolved in 2 mL drydimethylformamide. To this was added t-butyl bromoacetate (0.0175 mL,0.119 mmol) and freshly ground K₂CO₃ (0.025 g, 0.178 mmol.) Stirred at50° C., for one hour until starting material consumed. Concentrated offsome solvent, diluted with ethylacetate, washed with saturated NH₄Clsolution, concentrated organics to give crude product. Chromatographed(10 to 15% ethylacetate/hexanes) to give product 73 (0.0309 g, 0.05mmol, 84%.) ¹ H NMR (CDCl₃) δ 9.09 (dd, 1H), 8.97 (d, 1H), 7.92 (s, 1H),7.62 (d, 4H), 7.44 (m, 2H), 7.27 (m, 7 H), 7.05 (dd, 2H), 5.12 (s, 2H),4.83 (s, 2H), 1.38 (s, 9H.) MS: 619 (M+1)

Example 74

Tertiary Butyl ester 73 was dissolved in 0.5 mL of dichloromethane. Tothis was added 0.2 mL of triethylsilane and 0.1 mL of trifluoroaceticacid. Stirred at room temperature and after ten minutes complete by TLC.Concentrated off volatiles, azeotroped with toluene to give crude.Triturated with 1:1 diethylether/hexanes to give product 74 (0.0189 g,0.042 mmol, 84%.) ¹H NMR (CDCl₃) δ 9.05 (m, 2H), 7.72 (dd, 1H), 7.5 (dd,2H), 7.04 (dd, 2H), 5.22 (s, 2H), 4.84 (s, 2H), 1.44 (s, 9H.) MS: 453(M+1), 451 (M−1)

Example 75

Monophenol 45 (0.04 g, 0.079 mmol) was dissolved in 1 mL drydimethylformamide. To this was added 2-bromoacetamide (0.022 g 0.158mmol) and freshly ground K₂CO₃ (0.0345 g, 0.25 mmol.) Stirred at 60° C.,for three hours until starting material nearly consumed. Concentratedoff some solvent, diluted with ethylacetate, washed with saturatedNaHCO₃ solution, concentrated organics to give crude product.Chromatographed (10 to 50% ethylacetate/hexanes) to give product 75(0.0204 g, 0.0355 mmol, 46%.) ¹H NMR (CDCl₃) δ 9.15 (dd, 1H), 8.53 (d,1H), 7.96 (s, 1H), 7.6 (m, 4H), 7.45 (dd, 2H), 7.27 (m, 7H), 7.06 (dd,2H), 5.73 (br s, 1H), 4.84 (s, 2H), 4.77 (s, 2H.) MS: 562 (M−1)

Example 76

Amide 75 was dissolved in 0.5 mL of dichloromethane. To this was added0.2 mL of triethylsilane and 0.1 mL of trifluoroacetic acid. Stirred atroom temperature and after ten minutes complete by TLC. Concentrated offvolatiles, azeotroped with toluene to give crude. Triturated with 1:1diethylether/hexanes to give product 76 (0.0095 g, 0.024 mmol, 67%.) ¹HNMR (CD₃SOCD₃) δ 9.08 (dd, 1H), 8.93 (d, 1H), 7.87 (dd, 1H), 7.73 (br s,1H), 7.41 (dd, 2H), 7.19 (dd, 2H), 4.86 (s, 2H), 4.75 (s, 2H.) MS: 396(M−1), 394 (M−1)

Example 77

Monophenol 45 (2.9 g, 5.75 mmol) was dissolved in 20 mL drydimethylformamide. To this was added methyl iodide (3.58 mL, 57.5 mmol)and freshly ground K₂CO₃ (3.17 g, 23 mmol.) Stirred at 40° C. for onehour, until starting material consumed. Diluted with dichloromethane,washed with saturated NH₄Cl solution, 2.5% LiCl solution, concentratedorganics to give crude product. Chromatographed (15 to 55%ethylacetate/hexanes to give product 77 (2.54 g, 4.9 mmol, 85%.) ¹H NMR(CDCl₃) δ 9.1 (dd, 1H), 8.64 (dd, 1H), 7.91 (s, 1H), 7.62 (m, 5H), 7.46(dd, 2H), 7.27 (m, 7H), 7.05 (dd, 2H), 4.84 (s, 2H), 4.28 (s, 3H.) MS:519 (M+1)

Example 78

Methyl ether 77 was dissolved in 115 mL of dry tetrahydrofuran and 25 mLof dry methanol. To this was added three equivalents of a 0.5 M solutionof NaBH4 (29.4 mL, 14.7 mmol) in 2-methoxyethyl ether. After 15 hrs atroom temperature, concentrated off some solvent, diluted withdichloromethane, washed with 1M HCl solution with NaCl added,concentrated, chromatographed (15-66% ethlylacetate/hexanes) to giveoil. Triturated with hexane to give product 78 (1.3 g, 2.5 mmol, 68%.)¹H NMR (CD₃SOCD₃) δ 9.08 (dd, 1H), 8.5 (d, 1H), 7.89 (s, 1H), 7,75 (d,2H), 7.69 (dd, 1H), 7.63 (d, 2H), 7.42 (dd, 2H), 7.27 (m, 7H), 6.9 (d,1H), 5.92 (dd, 1H), 4.97 (d J=15 Hz, 1H), 4.45 (d J=15 Hz, 1H), 4.04 (s,3H.) MS: 521 (M+1)

Example 79

Aminal 78 was dissolved in 15 mL of dichloromethane. To this was added 2mL of triethylsilane and 1 mL of trifluoroacetic acid. Stirred at roomtemperature and after ten minutes complete by TLC. Concentrated offvolatiles, azeotroped with toluene to give crude. Triturated with 1:1diethylether/hexanes to give reduced product. Dissolved in 30 mL ofdichloromethane and cooled to 0° C. To this was added 4 mL oftriethylsilane and trimethylsilyltriflate (1.36 mL, 7.5 mmol.) Stirredvigorously for three minutes, then concentrated off volatiles, dilutedwith dichloromethane, washed quickly with saturated NaHCO₃ solution,concentrated organics to give crude product 79. Triturated with 1:1diethylether/hexanes to give product (0.806 g, 2.38 mmol, 95% for twosteps.) ¹H NMR (CDCl₃) δ 8.96 (dd, 1H), 8.50 (d, 1H), 7.56 (dd, 1H),7.37 (dd, 2H), 7.09 (dd, 2H), 4.78 (s, 2H), 4.51 (s, 2H), 3.98 (s, 3H).MS: 339 (M+1), 337 (M−1).

Example 80

Monophenol 45 (0.02 g, 0.0396 mmol) was dissolved in 1 mL drydichloromethane. To this was added at 0° C. triethylamine (0.0165 mL,0.1188 mmol) and dimethylcarbamoyl chloride (0.0054 mL, 0.0594 mmol).Catalytic amount of DMAP was also added. Stirred at room temperatureovernight. Dilute with dichloromethane, washed with saturated NaHCO₃solution and saturated NH₄Cl solution, concentrated to give crude.Triturated with 1:1 diethylether/hexanes and chromatographed (10%methanol/45% ethylacetate/45% hexanes) to give product 80 (0.012 g,0.0198 mmol, 50%.) ¹H NMR (CDCl₃) δ 9.12 (s, 1H), 8.4 (d, 1H), 7.97 (s,1H), 7.62 (d, 4H), 7.43 (dd, 2H), 7.27 (m, 7H), 7.05 (dd, 2H), 4.81 (s,2H), 3.26 (s, 3H), 3.09 (s, 3H.) MS: 576 (M+1)

Example 81

Carbamate 80 (0.012 g, 0.0198 mmol) was dissolved in 0.5 mL ofdichloromethane. To this was added 0.2 mL of triethylsilane and 0.1 mLof trifluoroacetic acid. Stirred at room temperature and after tenminutes complete by TLC. Concentrated off volatiles, azeotroped withtoluene to give crude. Triturated with 1:1 diethylether/hexanes to giveproduct 81 (0.0054 g, 0.013 mmol, 67%.) ¹H NMR (CDCl₃) δ 8.98 (s, 1H),8.49 (d, 1H), 7.7 (dd, 1H), 7.46 (dd, 2H), 7.03 (dd, 2H), 4.83 (s, 2H),3.31 (s, 3H), 3.12 (s, 3H). MS: 410 (M+1), 408 (M−1).

Example 82

Monophenol 45 (0.035 g, 0.0694 mmol) was dissolved in 1 mL drydichloroethane. To this was added triethylamine (0.038 mL, 0.277 mmol)and 3-chlorocarbonyl-1-methanesulfonyl-2-imidazolidinone (0.0314 g,0.1388 mmol Stirred at room temperature for five minutes. Dilate withdichloromethane, washed with saturated NaHCO₃ solution and saturatedNH₄Cl solution, dried (MgSO₄), concentrated to give crude.Chromatographed (10% methanol/45% ethylacetate/45% hexanes) to giveproduct 82 (0.036 g, 0.0518 mmol, 75%.) ¹ 1 NMR (CDCl₃) 9.16 (dd, 1H),8.49 (dd, 1H), 8.00 (s, 1H), 7.66 (dd, 1H), 7.61 (d, 4H), 7.40 (dd, 2H),7.27 (m, 6H), 7.05 (dd, 2H), 4.81 (s, 2H), 4.2 (dd, 2H), 4.08 (dd, 2H),3.92 (s, 3H). MS: 695 (M+1).

Example 83

Carbamate 82 (0.036 g, 0.0518 mmol) was dissolved in 0.5 mL ofdichloromethane. To this was added 0.2 mL of triethylsilane and 0.1 mLof trifluoroacetic acid. Stirred at room temperature and after tenminutes complete by TLC. Concentrated off volatiles, azeotroped withtoluene to give crude. Triturated with 1:1 diethylether/hexanes to giveproduct 83 (0.025 g, 0.047 mmol, 91%.) ¹H NMR (CDCl₃) δ 9.04 (d, 1H),8.58 (d, 1H), 7.75 (dd, 1H), 7.43 (dd, 2H), 7.04 (dd, 2H), 4.82 (s, 2H),4.22 (dd, 2H), 4.10 (dd, 2H). MS: 529 (M+1), 527 (M−1).

Example 84

Monophenol 45 (0.045 g, 0.089 mmol) was dissolved in 1 mL drydichloroethane. To this was added triethylamine (0.049 mL, 0.356 mmol)and 4-morpholine carbonyl chloride (0.0207 mL, 0.178 mmol.) Stirred atroom temperature for 1.5 hours. Dilute with dichloromethane, washed withsaturated NaHCO₃, concentrated to give crude. Chromatographed (15% to60% ethylacetate/hexanes) to give product 84 (0.039 g, 0.063 mmol, 71%.)¹H NMR (CDCl₃) 9.13 (dd, 1H), 8.40 (d, 1H), 7.98 (s, 1H), 7.62 (dd, 4H),7.4 (dd, 2H), 7.27 (m, 7H), 7.05 (dd, 2H), 4.81 (s, 2H), 3.84 (br s,6H), 3.62 (br s, 2H.) MS: 618 (M+1)

Example 85

Carbamate 84 (0.039 g, 0.063 mmol) was dissolved in 0.5 mL ofdichloromethane. To this was added 0.2 mL of triethylsilane and 0.1 mLof trifluoroacetic acid. Stirred at room temperature and after tenminutes complete by TLC. Concentrated off volatiles, azeotroped withtoluene to give crude. Triturated with 1:1 diethylether/hexanes to giveproduct 85 (0.014 g, 0.032 mmol, 51%.) ¹H NMR (CDCl₃) δ 9.0 (d, 1H),8.48 (d, 1H), 7.72 (dd, 1H), 7.49 (dd, 2H), 7.04 (dd, 2H), 4.83 (s, 2H),3.88 (br s, 6H), 3.66 (br s, 2H.) MS: 452 (M+1), 450 (M−1)

Example 86

Triflate 46 in benzene concentrated to give (0.048 g, 0.075 mmol) anddissolved in 1 mL dry tetrahydrofuran. To this was added freshly groundK₂CO₃ (0.069 , 0.5 mmol) and dimethylmalonate (0.017 mL, 0.15 mmol) andstirred at 500 C. After 15 hours, starting material consumed,concentrated to give oil. Chromatographed (5% to 30%ethylacetate/hexanes) to give product 86 (0.012 g, 0.0195 mmol, 26%.) ¹HNMR (CDCl₃) δ 9.09 (d, 1H), 8.51 (d, 1H), 8.12 (s, 1H), 7.65 (d, 4H),7.57 (dd, 1H), 7.48 (dd, 2H), 7.27 (m, 6H), 7.07 (dd, 2H), 4.85 (s, 2H),3.72 (6H.) MS: 619 (M+1)

Example 87

Di-ester 86 (0.008 g, 0.0129 mmol) was dissolved in 0.5 mL ofdichloromethane. To this was added 0.2 mL of triethylsilane and 0.1 mLof trifluoroacetic acid. Stirred at room temperature and after tenminutes complete by TLC. Concentrated off volatiles, azeotroped withtoluene to give crude. Triturated twice with 1:1 diethylether/hexanes togive product 87 (0.0022 g, 0,0049 mmol, 38%.) 3H NMR (CDCl₃) δ 8.95 (d,1H), 8.60 (d, 1H), 7.70 (dd, 1H), 7.55 (dd, 2H), 7.05 (dd, 2H), 4.87 (s,2H), 3.76 (s, 6H.) MS: 453 (M+1), 451 (M−1)

Example 88

Mono-phenol 12 (0.03 g, 0.06 mmol) was dissolved in 1 mL ofdichloroethane. To this was added triethylamine (0.033 mL, 0.24 mmol)and 2-oxo-1-imidazolidinecarbonyl chloride (0.0178 g, 0.12 mmol.)Catalytic amount of DMAP added, and stirred at room temperature forthree hours. Diluted with dichloromethane, washed with saturated NH₄Clsolution, concentrated to give crude. Chromatographed (10%ethylacetate/hexane to 10% medmanol/45% ethylacetate/45% hexanes) togive product 88 (0.0247 g, 0.0395 mmol, 68%.) ¹H NMR (CDCl₃) δ 8.96 (s,1H), 8.53 (d, 1H), 7.63 (dd, 1H), 7.43 (dd, 2H), 7.03 (dd, 2H), 4.81 (s,2H), 4.25 (dd, 2H), 3.69 (dd, 2H), 1.55 (m, 3H), 1.14 (d, 18H.) MS: 607(M+1)

Example 89

Urea 88 (0.024 g, 0.0395 mmol) was dissolved in 1 mL of drydichloromethane. To this was added ten equivalents (0.03 mL, 0.395 mmol)of trifluoroacetic acid. Stirred at room temperature, for fifteen hours.Concentrated off volatiles, azeotroped with toluene (2×), concentratedto give crude. Crude product triturated with 1:1 diethylether/hexanes togive product 89 (0.0119 g, 0.026 mmol, 67%.) ¹H NMR (CDCl₃) δ 9.00 (d,1H), 8.58 (d, 1H), 7.73 (dd, 1H), 7.47 (dd, 2H), 7.03 (dd, 2H), 4.83 (s,2H), 4.28 (dd, 2H), 3.70 (dd, 2H.) MS: 451 (M+1), 449 (M−1)

Example 90

Mono-phenol 12 (0.04 g, 0.08 mmol) was dissolved in 1.5 mL drytetrahydrofuran. To this was added triethylamine (0.0445 mL, 0.32 mmol)and bispentafluorophenyl carbonate (0.063 g, 0.16 mmol) and catalyticdimethylaminopyridine. Stirred at room temperature. After three hours,added methyl piperazine (0.04 mL, 0.36 mmol.) After two hours TLCindicated product formed however TIPSCl was removed. Diluted withdichloromethane, washed with saturated NH₄Cl solution, concentratedorganics to give crude. Dissolved in 1.5 mL dichloroethane, addedtriethylamine (0.11 mL, 0.8 mmol) and TIPSCl (0.085 mL, 0.4 mmol) andstirred at 50° C. Stirred for four hours until starting material wasconsumed. Diluted with dichloromethane, washed with saturated brine,concentrated organics to give crude. Chromatographed (50%ethylacetate/hexanes to 20% methanol/60% ethylacetate/20%hexanes) togive product 90 (0.027 g, 0.0435 mmol, 54% for two steps.) ¹H NMR(CDCl₃) δ 9.05 (d, 1H), 8.60 (d, 1H), 7.61 (dd, 1H), 7.41 (dd, 2H), 7.03(dd, 2H), 4.81 (s, 2H), 3.71 (br m, 8H), 2.43 (s, 3H), 1.60 (m, 3H),1.15 (d, 18H.) MS: 621 (M+1)

Example 91

Mono-carbamate 90 (0.027 g, 0.0435 mmol) was dissolved in 1 mL ofdichloromethane. To this was added trifluoroacetic acid (0.067 mL, 0.87mmol) and stirred at room temperature. After twenty hours, concentratedoff volatiles, azeotroped with toluene (2×), concentrated to give crude.Triturate with 1:1 diethylether/hexanes to give product 91 (0.0177 g,0.038 mmol, 87%.) ¹H NMR (CD₃SOCD₃) δ 9.09 (s, 1H), 8.71 (d, 1H), 7.67(dd, 1H), 7.42 (dd, 2H), 7.07 (dd, 2H), 4.81 (s, 2H), 3.45 (br m, 8H),2.90 (s, 3H.) MS: 465 (M+1), 463 (M−1)

Example 92

Mono-phenol 12 (0.04 g, 0.08 mmol) was dissolved in 1.5 mLdichloromethane. To this was added triethylamine (0.044 mL, 0.32 mmol),dimethylsulfamoyl chloride (0.017 mL, 0.16 mmol) and catalyticdimethylaminopyridine. Stirred at room temperature for 30 minutes.Diluted with dichloromethane, washed with saturated NH4Cl solution,concentrated organics to give crude. Chromatographed (25%ethylacetate/hexanes) to give product 92 (0.017 g, 0.02828 mmol, 35%.)¹H NMR (CDCl₃) δ 8.95 (d, 1H), 8.79 (d, 1H), 7.66 (dd, 1H), 7.45 (dd,2H), 7.03 (dd, 2H), 4.84 (s, 2H), 3.24 (s, 6H), 1.55 (m, 3H), 1.14 (d,18H.) MS: 602 (M+1)

Example 93

Mono-carbamate 92 (0.017 g, 0.02828 mmol) was dissolved in 1 mL ofdichloromethane. To this was added trifluoroacetic acid (0.044 mL,0.5657 mmol) and stirred at room temperature. After twenty hours,concentrated off volatiles, azeotroped with toluene (2×), concentratedto give crude. Triturate with 1.1 diethylether/hexanes to give product93 (0.0081 g, 0.018 mmol, 64%.) ¹H NMR (CDCl₃) δ 9.00 (d, 1H), (8.84 (d,1H), 7.76 (dd, 1H), 7.49 (dd, 2H), 7.03 (dd, 2H), 4.86 (s, 2H), 3.24 (s,6H.) MS: 446 (M+1), 444 (M−1)

Example 94

Mono-phenol 45 (0.04 g, 0.08 mmol) was dissolved in 1.5 mLtetrahydrofuran. To this was added diisopropylethylamine (0.052 mL, 0.3mmol), bis-pentafluorophenyl carbonate (0.047 g, 0.119 mmol) andcatalytic dimethylaminopyridine. Stirred at room temperature. After 75minutes, cooled to 0° C., n-butylamine (0.079 mL, 0.08 mmol) added.Stirred for 1.5 hours, then diluted with dichloromethane, washed withsaturated brine, 1 M HCl, concentrated organics to give crude.Chromatographed (25% ethylacetate/hexanes to give product 94 (0.0028 g,0.0048 mmol, 6%.) ¹H NMR (CDCl₃) δ 9.12 (d, 1H), 8.41 (d, 1H), 7.98 (s,1H), 7.61 (d, 4H), 7.43 (dd, 2H), 7.27 (m, 7H), 7.043 (dd, 2H), 5.37 (m,1H), 4.82 (s, 2H), 3.35 (q, 2H), 1.67 (m, 2H), 1.49 (m, 2H), 1.01 (t,3H.) MS: 604 (M+1)

Example 95

Carbamate 94 (0.006 g, 0.0099 mmol) was dissolved in 0.5 mL ofdichloromethane. To this was added 0.2 mL of triethylsilane and 0.1 mLof trifluoroacetic acid. Stirred at room temperature and after tenminutes complete by TLC. Concentrated off volatiles, azeotroped withtoluene to give crude which was triturated twice with 1:1diethylether/hexanes to give product 95 (0.0014 g, 0.003 mmol, 32%.) ¹HNMR (CDCl₃) δ 8.98 (s, 1H), 8.49 (d 1H), 7.68 (dd, 1H), 7.47 (dd, 2H),7.03 (dd, 2H), 5.40 (m, 1H), 4.83 (s, 2H), 3.38 (q, 2H), 3.15 (m, 2H),1.49 (m, 2H), 1.03 (t, 3H.) MS: 438 (M+1), 436 (M−1)

Example 96

Monophenol 45 (0.05 g, 0.099 mmol) was dissolved in 0.5 mL ofdichloromethane. To this was added triethylamine (0.03 mL, 0.2 mmol) andpyrrolidine carbonyl chloride (0.0214 mL, 0.2 mmol.) Stirred at 30° C.for fifteen hours. Diluted with dichloromethane, washed with 1 M HClsolution, concentrated organics to give crude. Chromatographed (20% to50% ethylacetate/hexanes) to give product 96 (0.033 g, 0.0555 mmol,57%.) ¹H NMR (CDCl₃) δ 9.11 (dd, 1H), 8.45 (d, 1H), 7.97 (s, 1H), 7.62(d, 5H), 7.40 (dd, 2H), 7.27 (m, 6H), 7.05 (dd, 2H), 4.81 (s, 2H), 3.75(dd, 2H), 3.54 (dd, 2H), 2.05 (m, 4H.) MS: 602 (M+1)

Example 97

Carbamate 96 (0.033 g, 0.055 mmol) was dissolved in 0.5 mL ofdichloromethane. Triethylsilane (0.2 mL) and of trifluoroacetic acid(0.1 mL) were added. The mixture was stirred at room temperature and wascomplete after ten minutes by TLC. The mixture was concentrated in vacuoand azeotroped with toluene to give a crude residue which was trituratedtwice with 1:1 diethylether/hexanes to give product 97 (0.0123 g, 0.028mmol, 51%). ¹H NMR (CDCl₃) δ 8.98 (d, 1H), 8.51 (d, 1H), 7.70 (dd, 1H),7.46 (dd, 2H), 7.03 (dd, 2H), 4.82 (s, 2H), 3.81 (dd, 2H), 3.57 (dd,2H), 2.09 (m, 4H.) MS: 436 (M+1), 434 (M−1)

Example 98

Monophenol 45 (0.03 g, 0.06 mmol) was dissolved in 1.5 mL ofdichloromethane. Triethylamine (0.033 mL, 0.238 mmol) anddiethylcarbamoyl chloride (0.015 mL, 0.119 mmol) were added. The mixturewas stirred at 60° C. for five hours. The mixture was diluted withdichloromethane, washed with 1 M HCl solution, and concentrated to givecrude product. The crude product was chromatographed (20% to 50%ethylacetate/hexanes) to give product 98 (0.0237 g, 0.040 mmol, 66%.) ¹HNMR (CDCl₃) δ 9.12 (s, 1H), 8.34 (d, 1H), 7.97 (s, 1H), 7.63 (d, 4H),7.40 (dd, 2H), 7.27 (m, 7H), 7.01 (dd, 2H), 4.81 (s, 2H), 3.61 (dd, 2H),3.50 (q, 2H), 1.41 (t, 3H), 1.37 (t, 3H.) MS: 604 (M+1)

Example 99

Carbamate 98 (0.023 g, 0.04 mmol) was dissolved in 0.5 mL ofdichloromethane. Triethylsilane (0.2 mL) and trifluoroacetic acid (0.1mL) were added. The mixture was stirred at room temperature and afterten minutes was complete by TLC. Concentrated off volatiles, azeotropedwith toluene to give crude. Triturated twice with 1:1diethylether/hexanes to give product 99 (0.01 g, 0.024 mmol, 60%.) ¹HNMR (CDCl₃) δ 8.98 (d, 1H), 8.45 (d, 1H), 7.70 (dd, 1H), 7.48 (dd, 2H),7.03 (dd, 2H), 4.82 (s, 2H), 3.67 (q, 2H), 3.48 (q, 2H), 1.46 (t, 3H),1.32 (t, 3H.) MS: 438 (M+1), 436 (M−1)

Example 100

Trimethylsilyl ether 44 (0.022 g, 0.0373 mmol) was dissolved in 0.5 mLdry tetrahydrofuran. To this was added triethylamine (0.031 mL, 0.2238mmol) and 1 M tetrabutylammonium fluoride solution in tetrahydrofuran(0.0559 mL, 0.0559 mmol.) Stirred at room temperature 10 minutes untilstarting material consumed. Then added catalytic amount ofdimethylaminopyridine and 2-oxo-1-imidazolidinecarbonyl chloride (0.022g, 0.1492 mmol.) Stirred at room temperature for three hours, thendiluted with dichloromethane, washed with 1M HCl solution, saturatedNaHCO₃, saturated brine, concentrated to give crude. Chromatographed(50% ethylacetate/hexanes to 1:1:1 methanol, ethylacetate, hexanes) togive product 100 (0.0197 g, 0.031 mmol, 88%.) ¹H NMR (CDCl₃) δ 9.04 (dd,1H), 8.31 (d, 1H), 8.02 (s, 1H), 7.73 (d, 4H), 7.53 (dd, 1H), 7.27 (m,6H), 7.04 (dd, 2H), 5.00 (s, 1H) 4.80 (s, 2H), 4.10 (dd, 2H), 3.64 (dd,2H.) MS: 603 (M+1)

Example 101

Carbamate 100 (0.019 g, 0.031 mmol) was dissolved in 0.5 mL ofdichloromethane. To this was added 0.2 mL of triethylsilane and 0.1 mLof trifluoroacetic acid. Stirred at room temperature and after tenminutes complete by TLC. Concentrated off volatiles, azeotroped withtoluene to give crude. Triturated twice with 1:1 diethylether/hexanes togive product 101 (0.006 g, 0.011 mmol, 35%.) ¹H NMR (CD₃SOCD₃) δ 8.98(s, 1H), 8.48 (d, 1H), 7.77 (dd, 1H), 7.72 (s, 1H), 7.36 (dd, 2H), 7.22(dd, 2H), 4.70 (s, 2H), 4.37 (s, 2H), 4.03 (dd, 2H), 3.41 (dd, 2H.) ¹⁹FNMR: −74.6 MS: 437 (M+1), 435 (M−1)

Example 102

Trimethylsilylethyl ether 44 (0.03 g, 0.0508 mmol) was dissolved in 0.5mL dry tetrahydrofuran. Triethylamine (0.042 mL, 0.3048 mmol) and 1 Mtetrabutylammonium fluoride solution in tetrahydrofuran (0.1016 mL,0.1016 mmol) were added and stirred at room temperature for 10 minutesuntil starting material was consumed. A catalytic amount ofdimethylaminopyridine was added, followed by diethylcarbamoyl chloride(0.026 mL, 0.2032 mmol). The mixture was stirred at room temperature forfour hours, then diluted with dichloromethane, washed with 1M HClsolution, saturated NaHCO₃, saturated brine, and concentrated to thecrude product. Chromatographed (25% to 50% ethylacetate/hexanes) to giveproduct 102 (0.014 g, 0.024 mmol, 47%.) ¹H NMR (CDCl₃) δ 9.04 (s, 1H),8.11 (d, 1H), 8.03 (s, 1H), 7.76 (d, 4H), 7.51 (dd, 1H), 7.27 (m, 8H),7.08 (dd, 2H), 4.80 (s, 2H), 4.21 (s, 2H), 3.53 (q, 2H), 3.40 (q, 2H),1.33 (t, 3H), 1.23 (t, 3H.) MS: 590 (M+1)

Example 103

Carbamate 102 (0.01 g, 0.0169 mmol) was dissolved in 0.5 mL ofdichloromethane. To this was added 0.2 mL of triethylsilane and 0.1 mLof trifluoroacetic acid. Stirred at room temperature and after tenminutes complete by TLC. Concentrated off volatiles, azeotroped withtoluene to give crude. Triturated twice with 1:1 diethylether/hexanes togive product 103 (0.0073 g, 0.014 mmol, 80%.) ¹H NMR (CDCl₃) δ 9.01 (s,1H), 8.23 (d, 1H), 7.60 (dd, 1H), 7.33 (dd, 2H), 7.09 (dd, 2H), 4.77 (s,2H), 4.37 (s, 2H), 3.56 (q, 2H), 3.43 (q, 2H), 1.37 (t, 3H), 1.26 (t,3H.) ¹⁹F NMR: −76.2 MS: 424 (M+1), 422 (M−1)

Example 104

Trimethylsilylethyl ether 44 (0.03 g, 0.0508 mmol) was dissolved in 0.5mL dry tetrahydrofuran. To this was added triethylamine (0.042 mL,0.3048 mmol) and 1 M tetrabutylammonium fluoride solution intetrahydrofuran (0.1016 mL, 0.1016 mmol.) Stirred at room temperature 10minutes until starting material consumed. Then added catalytic amount ofdimethylaminopyridine and dimethylcarbamoyl chloride (0.0187 mL, 0.2032mmol.) Stirred at room temperature for six hours, then diluted withdichloromethane, washed with 1 M HCl solution, saturated NaHCO₃,saturated brine, concentrated to give crude. Chromatographed (20% to 50%ethylacetate/hexanes) to give product 104 (0.014 g, 0.024 mmol, 48%.) ¹HNMR (CDCl₃) δ 9.04 (d, 1H), 8.14 (d, 1H), 8.03 (s, 1H), 7.75 (d, 4H),7.51 (dd, 1H), 7.27 (m, 8H), 7.16 (dd, 2H), 4.80 (s, 2H0, 4.23 (s, 2H),3.19 (s, 3H), 3.02 (s, 3H.) MS: 562 (M+1)

Example 105

Carbamate 104 (0.012 g, 0.021 mmol) was dissolved in 0.5 mL ofdichloromethane. To this was added 0.2 mL of triethylsilane and 0.1 mLof trifluoroacetic acid. Stirred at room temperature and after tenminutes complete by TLC. Concentrated off volatiles, azeotroped withtoluene to give crude. Triturated twice with 1:1 diethylether/hexanes togive product 105 (0.0068 g, 0.017 mmol, 82%.) ¹H NMR (CDCl₃) δ 8.96 (s,1H), 8.25 (d, 1H), 7.59 (dd, 1H), 7.36 (dd, 2H), 7.09 (dd, 2H), 4.77 (s,2H), 4.38 (s, 2H), 3.24 (s, 3H), 3.06 (s, 3H.) MS: 396 (M+1), 394 (M−1)

Example 106

Trimethylsilylethyl ether 44 (0.03 g, 0.0508 mmol) was dissolved in 0.5mL dry tetrahydrofuran. To this was added triethylamine (0.0282 mL,0.2032 mmol) and 1M tetrabutylammonium fluoride solution intetrahydrofuran (0.076 mL, 0.076 mmol.) Stirred at room temperature 10minutes until starting material consumed. After fifteen minutes, dilutedwith dichloromethane, washed with washed with 1M HCl solution, saturatedNaHCO₃, saturated brine, concentrated to give crude. Diluted in 1 mLdichloromethane. To this was added triethylamine (0.028 mL, 0.2032mmol), para-nitrochloroformate (0.02 g, 0.1016 mmol) and catalyticdimethylaminopyridine. Stirred at room temperature for 30 minutes, thendiluted with dichloromethane, washed with saturated NH₄Cl solution,concentrated organics to give crude. Chromatographed (50%ethylacetate/hexanes) to give product 106 (0.009 g, 0.0137 mmol, 27%) ¹HNMR (CDCl₃) δ 9.10 (s, 1H), 8.16 (d, 2H), 8.10 (s, 1H), 7.71 (d, 4H),7.53 (dd, 1H), 7.27 (m, 9H), 7.09 (dd, 2H), 6.93 (d, 2H), 4.79 (s, 2H),4.23 (s, 2H.) MS: 656 (M+1)

Example 107

Carbonate 106 (0.009 g, 0.0137 mmol) was dissolved in 0.5 mLdichloromethane. To this was added triethylamine (0.0282 mL, 0.2032mmol) and n-butylamine (0.01 mL, 0.1016 mmol) and stirred at roomtemperature. After 15 minutes, starting material consumed. Diluted withdichloromethane, washed with 1M HCl solution, saturated brine,concentrated to give crude. Chromatographed (30% ethylacetate/hexanes)to give product 107 (0.0075 g, 0.012 mmol, 88%.) ¹H NMR (CDCl₃) δ 9.02(s, 1H), 8.15 (d, 1H), 8.04 (s, 1H), 7.75 (d, 4H), 7.50 (dd, 1H), 7.27(m, 6H), 7.08 (dd, 2H), 5.18 (s, 1H), 4.80 (s, 2H), 4.21 (s, 2H), 3.31(q, 2H), 1.59 (m, 2H), 1.41 (m, 2H), 0.99 (t, 3H.) MS: 590 (M+1)

Example 108

Carbamate 107 (0.007 g, 0.012 mmol) was dissolved in 0.5 mL ofdichloromethane. To this was added 0.2 mL of triethylsilane and 0.1 mLof trifluoroacetic acid. Stirred at room temperature and after tenminutes complete by TLC. Concentrated off volatiles, azeotroped withtoluene to give crude. Triturated twice with 1:1 diethylether/hexanes togive product 108 (0.0028 g, 0.0066 mmol, 56%.) ¹H NMR (CDCl₃) δ 8.98 (s,1H), 8.27 (d, 1H), 7.59 (dd, 1H), 7.31 (dd, 2H), 7.06 (dd, 2H), 5.19 (s,1H), 4.77 (s, 2H), 4.37 (s, 2H), 3.32 (q, 2H), 1.65 (m, 2H), 1.44 (m,2H), 1.01 (t, 3H) MS: 424 (M+1), 422 (M−1)

Example 109

Trimethylsilylethyl ether 44 (0.01 g, 0.0169 mmol) was dissolved in 0.5mL dry tetrahydrofuran. To this was added triethylamine (0.014 mL,0.0339 mmol) and 1 M tetrabutylammonium fluoride solution intetrahydrofuran (0.0339 mL, 0.0339 mmol.) Stirred at room temperature 10minutes until starting material consumed. Diluted with dichloromethane,washed with washed with 1M HCl solution, saturated NaHCO₃, saturatedbrine, concentrated to give crude. Dissolved in 0.5 mL dichloromethane,added catalytic dimethylaminopyridine, triethylamine (0.042 mL, 0.1017mmol) and cooled to 0° C. To this was added a 1 M solution oftriphosgene in dichloromethane (0.1017 mL, 0.1017 mmol) and stirred 30minutes. Methyl piperazine (0.0168 mL, 0.1521 mmol) was then added andstirred at room temperature for fifteen minutes. Diluted withdichloromethane, washed with brine, concentrated volatiles to givecrude. Chromatographed (50% ethylacetate/hexanes to 10%methanol/ethylacetate) to give product 109 (0.0055 g, 0.009 nmmol, 53%.)¹H NMR (CDCl₃) δ 9.04 (d, 1H), 8.10 (d, 1H), 8.03 (s, 1H), 7.75 (d, 4H),7.52 (dd, 1H), 7.27 (m, 8H), 7.05 (dd, 2H), 4.80 (s, 2H), 4.22 (s, 2H),3.77 (br s, 2H), 3.58 (br s, 2H), 2.48 (br s, 4H), 2.37 (s, 3H) MS: 617(M+1)

Example 110

Carbamate 109 (0.007 g, 0.01136 mmol) was dissolved in 0.5 mL ofdichloromethane. To this was added 0.2 mL of triethylsilane and 0.1 mLof trifluoroacetic acid. Stirred at room temperature and after tenminutes complete by TLC. Concentrated off volatiles, azeotroped withtoluene to give crude. Triturated twice with 1:1 diethylether/hexanes togive product 110 (0.004 g, 0.007 mmol, 63%.) ¹H NMR (CDCl₃) δ 9.00 (s,1H), 8.11 (d, 1H), 7.59 (dd, 1H), 7.35 (dd, 2H), 7.08 (dd, 2H), 4.78 (s,2H), 4.35 (s, 2H), 3.50 (br m, 8H), 2.93 (s, 3H.), ¹⁹F NMR: −76.2 MS:451 (M+1), 449 (M−1)

Example 111

Trimethylsilylethyl ether 44 (0.02 g, 0.0339 mmol) was dissolved in 0.5mL dry tetrahydrofuran. Triethylamine (0.0188 mL, 0.135 mmol) and 1 Mtetrabutylammonium fluoride solution in tetrahydrofuran (0.0678 mL,0.0678 mmol) were added. The mixture was stirred at room temperature for10 minutes until starting material consumed. The mixture was dilutedwith dichloromethane, washed with 1M HCl solution, saturated NaHCO₃,saturated brine, and concentrated to give crude. The crude residue wasdissolved in 0.5 mL dichloromethane, and catalyticdimethylaminopyridine, triethylamine (0.0188 mL, 0.135 mmol) and ethylisocyanatoacetate (Aldrich, St. Louis, Mo., 0.011 mL, 0.1017 mmol) wereadded and stirred at room temperature (Satchell and Satchell, Chem. Soc.Rev. (1975) 4:231-250; R. G. Arnold et al., Chem. Soc. (1957) 57:47-76).After four hours, starting material was consumed. The mixture wasdiluted with dichloromethane, washed with 1M HCl, brine, andconcentrated in vacuo to give crude product. The crude product waschromatographed on silica gel (10% to 50% ethylacetate/hexanes) to giveproduct 111 (0.0118 g, 0.156 mmol, 46%) ¹H NMR (CDCl₃) δ 9.07 (d, 1H),8.73 (s, 1H), 8.17 (d, 1H), 8.08 (s, 1H), 7.76 (d, 4H), 7.57 (dd, 1H),7.27 (m, 8H), 7.08 (dd, 2H), 4.81 (s, 2H), 4.74 (s, 2H), 4.20 (m, 4H),4.07 (d, 4H), 1.27 (m, 6H). MS: 749 (M+1), 747 (M−1).

Example 112

Carbamate 111 (0.01 g, 0.0177 mmol) was dissolved in 0.5 mL ofdichloromethane. To this was added 0.2 mL of triethylsilane and 0.1 mLof trifluoroacetic acid. Stirred at room temperature and after tenminutes complete by TLC. Concentrated off volatiles, azeotroped withtoluene to give crude. Triturated twice with 1:1 diethylether/hexanes togive product 112 (0.0056 g, 0.0095 mmol, 54%.) ¹H NMR (CDCl₃) δ 8.99 (s,1H), 8.76 (s, 1H), 8.27 (d, 1H), 7.63 (dd, 1H), 7.35 (dd, 2H), 7.09 (dd,2H), 4.79 (d, 4H), 4.33 (d, 2H), 4.23 (m, 4H), 4.09 (d, 2H), 1.30 (m,6H.) MS: 583 (M+1), 581 (M−1)

Example 113

Trimethylsilylethyl ether 44 (0.02 g, 0.0339 mmol) was dissolved in 0.5mL dry tetrahydrofuran. To this was added triethylamine (0.019 mL, 0.14mmol) and 1 M tetrabutylammonium fluoride solution in tetrahydrofuran(0.0678 mL, 0.0678 mmol.) Stirred at room temperature 10 minutes untilstarting material consumed. Diluted with dichloromethane, washed withwashed with 1M HCl solution, saturated NaHCO₃, saturated brine,concentrated to give crude. Dissolved in 0.5 mL dichloromethane, addedcatalytic dimethylaminopyridine, triethylamine (0.019 mL, 0.14 mmol) andcooled to 0° C. To this was added a 1M solution of triphosgene indichloromethane (0.0678 mL, 0.0678 mmol) and stirred 60 minutes.Morpholine (0.009 mL, 0.1016 mmol) was then added and stirred at roomtemperature for 30 minutes. Diluted with dichoromethane, washed with 1MHCl, brine, concentrated volatiles to give crude. Chromatographed (40%ethylacetate/hexanes to 60% ethylacetate/hexanes) to give product 113(0.0176 g, 0.028 mmol, 86%.) ¹H NMR (CDCl₃) δ 9.05 (d, 1H), 8.09 (d,1H), 8.04 (s, 1H), 7.75 (d, 4H), 7.53 (dd, 1H), 7.27 (m, 8H), 7.06 (dd,2H), 4.81 (s, 1H), 4.23 (s, 2H), 3.78 (br s, 6H), 3.56 (br s, 2H.) MS:604 (M+1), 602 (M−1)

Example 114

Carbamate 113 (0.017 g, 0.028 mmol) was dissolved in 0.5 mL ofdichloromethane. To this was added 0.2 mL of triethylsilane and 0.1 mLof trifluoroacetic acid. Stirred at room temperature and after tenminutes complete by TLC. Concentrated off volatiles, azeotroped withtoluene to give crude. Triturated twice with 1:1 diethylether/hexanes togive product 114 (0.0085 g, 0.015 mmol, 55%.) ¹H NMR (CDCl₃) δ 9.02 (s,1H), 8.24 (d, 1H), 7.62 (dd, 1H), 7.33 (dd, 2H), 7.07 (dd, 2H), 4.78 (s,2H), 4.39 (s, 2H), 3.82 (br s, 6H), 3.60 (br s, 2H.) ¹⁹F NMR: −76.2 MS:438 (M+1), 436 (M−1)

Example 115

Trimethylsilylethyl ether 44 (0.02 g, 0.0339 mmol) was dissolved in 0.5mL dry tetrahydrofuran. To this was added diisopropylethylamine (0.024mL, 0.135 mmol) and 1 M tetrabutylammonium fluoride solution intetrahydrofuran (0.0678 mL, 0.0678 mmol.) Stirred at room temperature 10minutes until starting material consumed. Diluted with dichoromethane,washed with washed with 1M HCl solution, saturated NaHCO₃, saturatedbrine, concentrated to give crude. Dissolved in 0.5 mL dichloromethane,added catalytic dimethylaminopyridine, diisopropylethylamine (0.024 mL,0.135 mmol) and cooled to 0° C. To this was added a 1M solution oftriphosgene (bis[trichloromethyl]carbonate) in dichloromethane (0.0678mL, 0.0678 mmol) and stirred 45 minutes. Dimethylhydrazine (0.01 mL,0.135 mmol) was then added and stirred at room temperature for 20minutes. Diluted with dichloromethane, washed with saturated NH₄Clsolution, concentrated volatiles to give crude. Chromatographed (10%ethylacetate/hexanes to 60% ethylacetate/hexanes) and purified bypreparatory TLC plate (60% ethylacetate/hexanes) to give product 115(0.004 g, 0.0069 mmol, 20%.) ¹H NMR (CDCl₃) δ 9.05 (d, 1H), 8.11 (d,1H), 8.04 (s, 1H), 7.75 (d, 4H), 7.5 (dd, 1H), 7.27 (m, 8H), 7.07 (dd,2H), 6.14 (s, 1H), 4.80 (s, 2H), 4.23 (s, 2H), 2.70 (6H.) MS: 577 (M+1)

Example 116

Carbamate 115 (0.009 g, 0.0156 mmol) was dissolved in 0.5 mL ofdichloromethane. To this was added 0.2 mL of triethylsilane and 0.1 mLof trifluoroacetic acid. Stirred at room temperature and after tenminutes complete by TLC. Concentrated off volatiles, azeotroped withtoluene to give crude. Triturated twice with 1:1 diethylether/hexanes togive product 116 (0.003 g, 0.0057 mmol, 37%.) ¹H NMR (CDCl₃) δ 8.96 (s,1H), 8.24 (d, 1H), 7.56 (dd, 1H), 7.33 (dd, 2H), 7.06 (dd, 2H), 4.76 (s,2H), 4.39 (s, 2H), 2.74 (s, 3H.) ¹⁹F NMR: −76.1 MS: 411 (M+1), 409 (M−1)

Example 117

Trimethylsilylethyl ether 44 (0.02 g, 0.0339 mmol) was dissolved in 0.5mL dry tetrahydrofuran. To this was added triethylamine (0.0188 mL,0.135 mmol) and 1 M tetrabutylammonium fluoride solution intetrahydrofuran (0.0678 mL, 0.0678 mmol.) Stirred at room temperature 10minutes until starting material consumed. Diluted with dichloromethane,washed with washed with 1M HCl solution, saturated, saturated brine,concentrated to give crude. Dissolved in 0.5 mL dichoromethane, addedcatalytic dimethylaminopyridine₇ triethylamine (0.0188 mL, 0.135 mmol)and methyl (s)-(−)-2-isocyanato-3-methyl butyrate (0.0048 mL, 0.0339mmol) and stirred at room temperature. After 4.5 hours, startingmaterial consumed. Diluted with dichloromethane, washed with saturatedNH₄Cl solution, concentrated organics to give crude. Chromatographed(10% to 50% ethylacetate/hexanes) to give product 117 (0.0085 g, 0.013mmol, 39%.) ¹H NMR (CDCl₃) δ 9.03 (s, 1H), 8.17 (d, 1H), 8.05 (s, 1H),7.75 (4H), 7.52 (dd, 1H), 7.27 (m, 8H), 7.07 (dd, 2H), 5.70 (d, 1H),4.80 (s, 2H), 4.21 (s, 2H), 3.79 (s, 3H), 2.28 (dsp, 1H), 1.03 (d, 3H),0.98 (d, 3H.) MS: 649 (M+1)

Example 118

Carbamate 117 (0.004 g, 0.006 mmol) was dissolved in 0.5 mL ofdichloromethane. To this was added 0.2 mL of triethylsilane and 0.1 mLof trifluoroacetic acid. Stirred at room temperature and after tenminutes complete by TLC. Concentrated off volatiles, azeotroped withtoluene to give crude. Triturated twice with 1:1 diethylether/hexanes togive product 118(0.0027 g, 0,0046 mmol, 76%.) ¹H NMR (CDCl₃) δ 9.00 (S,1H), 8.31 (d, 1H), 7.60 (dd, 1H), 7.33 (dd, 2H), 7.09 (dd, 2H), 5.76 (d,1H), 4.77 (s, 2H), 4.36 (s, 2H), 3.81 (s, 3H), 2.28 (dsp, 1H), 1.06 (d,3H), 1.00 (d, 3H.) ¹⁹F NMR: −76.2 MS: 482 (M+1), 480 (M−1)

Example 119

Trimethylsilylethyl ether 44 (0.2 g, 0.339 mmol) was dissolved in 3 mLdry tetrahydrofuran. To this was added triethylamine (0.139 mL, 1 mmol)and 1 M tetrabutylammonium fluoride solution in tetrahydrofuran (0.0678mL, 0.0678 mmol.) Stirred at room temperature 10 minutes until startingmaterial consumed. Diluted with dichloromethane, washed with washed with1M HCl solution, saturated brine, concentrated to give crude. Dissolvedin 3 mL dichloromethane, added catalytic dimethylaminopyridine,triethylamine (0.754 mL, 5.4 mmol) and cooled to 0° C. To this was addeda 1M solution of triphosgene in dichloromethane (0.1356 mL, 0.1356 mmol)and stirred 50 minutes. BOC-piperazine (0.37 g, 2 mmol) was then addedand stirred at room temperature for 30 minutes. Diluted withdichloromethane, washed with 1M HCl, brine, concentrated volatiles togive crude. Chromatographed (10% to 30% acetone/toluene) to give product119 (0.1158 g, 0.166 mmol, 49%.) ¹H NMR (CDCl₃) δ 9.04 (d, 1H), 8.09 (d,1H), 8.04 (s, 1H), 7.75 (d, 4H), 7.50 (dd, 1H), 7.27 (m, 8H), 7.05 (dd,2H), 4.80 (s, 2H), 4.22 (s, 2H), 3.73 (br s, 2H), 3.53 (br s, 4H), 1.51(s, 9H.) MS: 688 (M+1)

Example 120

Carbamate 119 (0.057 g, 0.082 mmol) was dissolved in 1 L ofdichloromethane. To this was added 0.4 mL of triethylsilane and 0.2 mLof trifluoroacetic acid. Stirred at room temperature and after tenminutes complete by TLC. Concentrated off volatiles, azeotroped withtoluene to give crude. Then dissolved in 1 mL dichloromethane, 1 mltrifluoroacetic acid. Stirred at room temperature for one hour.Concentrated off volatiles, azeotroped with toluene to give crude.Triturated twice with 1:1 diethylether/hexanes to give product 120(0.0317 g, 0.059 mmol, 72%.) ¹H NMR (CD₃SOCD₃) δ 8.97 (br m, 2H), 8.40(d, 1H), 7.75 (dd, 1H), 7.35 (dd, 2H), 7.23 (dd, 2H), 4.71 (s, 2H), 4.38(s, 2H), 3.91 (br s, 2H), 3.24 (br s, 4H.) ¹⁹F NMR: −74.5 MS: 437 (M+1),435 (M−1)

Example 121

Trimethylsilylethyl ether 44 (0.035 g, 0.0596 mmol) was dissolved in 0.8mL dry tetrahydrofuran. To this was added triethylamine (0.05 mL, 0.358mmol) and 1 M tetrabutylammonium fluoride solution in tetrahydrofuran(0.119 mL, 0.119 mmol.) Stirred at room temperature 10 minutes untilstarting material consumed. Diluted with dichloromethane, washed withwashed with 1M HCl solution, saturated brine, concentrated to givecrude. Dissolved in 0.8 mL dichloromethane, added triethylamine (0.05mL, 0.358 mmol) and ethyl isocyanate (0.0046 mL, 0.0595 mmol) andstirred at room temperature. After 6 hours, starting material consumed.Diluted with dichloromethane, washed with saturated brine, concentratedorganics to give crude. Chromatographed (10% to 50%ethylacetate/hexanes) to give product 121 (0.0112 g, 0.023 mmol, 39%.)¹H NMR (CDCl₃) δ 9.05 (s, 1H), 8.17 (d, 1H), 8.04 (s, 1H), 7.76 (d, 4H),7.50 (dd, 1H), 7.27 (m, 8H), 7.05 (dd, 2H), 4.80 (s, 2H), 4.23 (s, 2H),3.33 (q, 2H), 1.27 (t, 3H.) MS: 562 (M+1)

Example 122

Carbamate 121 (0.0112 g, 0.023 mmol) was dissolved in 0.5 mL ofdichloromethane. To this was added 0.2 mL of triethylsilane and 0.1 mLof trifluoroacetic acid. Stirred at room temperature and after tenminutes complete by TLC. Concentrated off volatiles, azeotroped withtoluene to give crude. Triturated twice with 1:1 diethylether/hexanes togive product 122 (0.0033 g, 0.0076 mmol, 33%.) ¹H NMR (CDCl₃) δ 9.06 (s,1H), 8.37 (d, 1H), 7.64 (dd, 1H), 7.33 (dd, 2H), 7.06 (dd, 2H), 5.24 (s,1H), 4.77 (s, 2H), 4.39 (s, 2H), 3.38 (q, 2H), 1.30 (t, 3H.) ¹⁹F NMR:−76.2 MS: 397 (M+1), 395 (M−1)

Example 123

N-Methyl piperazine (0.33 mL, 3 mmol) was added slowly and with cautionto a mixture of sulfuryl chloride (0.72 mL, 9 mmol) in 6 mL ofacetonitrile. The solution was heated to reflux for 15 hours. Afterstarting material consumed, solution concentrated to oil, azeotropedwith toluene (2×), concentrated to give crude product which wastriturated with diethylether to give the product 123 as a pale brownsolid (0.5 g, 71%.) ¹H NMR (CD₃SOCD₃) δ 3.90 (br s, 2H), 3.59 (br s,2H.), 3.38 (br. S, 4H), 2.67 (s, 3H); MS: 200 (M+1).

Example 124

Trimethylsilylethyl ether 44 (0.03 g, 0.0508 mmol) was dissolved in 0.5mL dry tetrahydrofuran. Triethylamine (0.021 mL, 0.1525 mmol) and 1 Mtetrabutylammonium fluoride solution in tetrahydrofuran (0.1016 mL,0.1016 mmol.) were added. The mixture was stirred at room temperature 10minutes until starting material was consumed, then diluted withdichloromethane, washed with washed with 1 M HCl solution, saturatedbrine, and concentrated. The crude product was dissolved in 0.5 mLdichloromethane. Catalytic diethylaminopyridine, triethylamine (0.035mL, 0.254 mmol) and methyl piperazine sulfamoyl chloride HCl salt 123(0.024 g, 0.1016 mmol) were added and stirred at room temperature. After15 hours, starting material was consumed. The mixture was diluted withdichloromethane, washed with saturated brine, and concentrated organicsto give crude product which was chromatographed (1% to 10%methanol/dichloromethane) to give product 124 (0.016 g, 0.0246 mmol,48%.) ¹H NMR (CDCl₃) δ 9.07 (s, 1H), 8.38 (d, 1H), 8.08 (s, 1H), 7.75(d, 4H), 7.55 (dd, 1H), 7.27 (m, 8H), 7.08 (dd, 2H), 4.81 (s, 2H), 4.46(s, 2H), 3.51 (br s, 4H), 2.54 (br s, 4H), 3.35 (s, 3H.) MS: 653 (M+1)

Example 125

Sulfamate 124 (0.016 g, 0.0246 mmol) was dissolved in 0.5 mL ofdichloromethane. To this was added 0.2 mL of triethylsilane and 0.1 mLof trifluoroacetic acid. Stirred at room temperature and after tenminutes complete by TLC. Concentrated off volatiles, azeotroped withtoluene to give crude. Triturated twice with 1:1 diethylether/hexanes togive product 125 (0.008 g, 0.0133 mmol, 54%.) ¹H NMR (CDCl₃) δ 9.02 (s,1H), 8.37 (d, 1H), 7.67 (dd, 1H), 7.33 (dd, 2H), 7.06 (dd, 2H), 4.80 (s,2H), 4.57 (s, 2H), 3.95 (br s, 4H), 3.29 (br s, 4H), 2.89 (s, 3H.) ¹⁹FNMR: −76.2 MS: 487 (M+1), 485 (M−1)

Example 126

Morpholine (0.436 mL, 5 mmol) was added slowly and with caution to amixture of sulfinyl chloride (1.205 mL, 15 mmol) in 5 mL acetonitrile.Heated to reflux and stirred for 24 hours. After starting materialconsumed, solution concentrated to oil, azeotroped with toluene (2×),concentrated to give crude product 126 stored as a 2M solution indichloromethane (0.999 g, 5 mmol, 100%.) ¹H NMR (CD₃SOCD₃) δ 3.80 (br s,4H), 3.28 (br s, 4H.) MS: 186 (M+1)

Example 127

Trimethylsilylethyl ether 44 (0.027 g, 0.0457 mmol) was dissolved in 0.5mL dry tetrahydrofuran. To this was added triethylamine (0.025 mL,0.1828 mmol) and 1 M tetrabutylammonium fluoride solution intetrahydrofuran (0.0915 mL, 0.0915 mmol.) Stirred at room temperature 10minutes until starting material consumed. Diluted with dichloromethane,washed with washed with 1M HCl solution, saturated brine, concentratedto give crude. Dissolved in 0.5 mL dichloromethane, added catalyticdimethylaminopyridine, triethylamine (0.025 mL, 0.1828 mmol) and 2 Mmorpholine sulfamoyl chloride solution 126 in dichloromethane (0.05 g,0.10 mmol) and stirred at room temperature. After 1.5 hours, startingmaterial consumed. Diluted with dichloromethane, washed with saturatedbrine, concentrated organics to give crude. Chromatographed (10% to 40%ethylacetate/hexanes) to give product 127 (0.0199 g, 0.031 mmol, 68%.)¹H NMR (CDCl₃) δ 9.07 (s, 1H), 8.35 (d, 1H), 8.09 (s, 1H), 7.75 (d, 4H),7.56 (dd, 1H), 7.27 (m, 8H), 7.05 (dd, 2H), 4.82 (s, 2H), 4.46 (s, 2H),3.81 (m, 4H), 3.75 (m, 4H), 3.48 (m, 4H), 3.27 (m, 4H.) MS: 790 (M+1)

Example 128

Sulfamate 127 (0.095 g, 0.012 mmol) was dissolved in 0.5 mL ofdichloromethane. To this was added 0.2 mL of triethylsilane and 0.1 mLof trifluoroacetic acid. Stirred at room temperature and after tenminutes complete by TLC. Concentrated off volatiles, azeotroped withtoluene to give crude. Triturated twice with 1:1 diethylether/hexanes togive product 128 (0.0054 g, 0.0086 mmol, 71%.) ¹H NMR (CDCl₃) δ 9.00 (s,1H), 8.45 (d, 1H), 7.65 (dd, 1H), 7.33 (dd, 2H), 7.10 (dd, 2H), 4.79 (s,2H), 4.59 (s, 2H), 3.86 (m, 4H), 3.76 (m, 4H), 3.59 (m, 4H), 3.28 (m,4H.) MS: 624 (M+1), 622 (M−1)

Example 129

Trimethylsilylethyl ether 44 (0.1 g, 0.169 mmol) was dissolved in 2 mLdry tetrahydrofuran. To this was added triethylamine (0.094 mL, 0.676mmol) and 1 M tetrabutylammonium fluoride solution in tetrahydrofuran(0.339 mL, 0.339 mmol.) Stirred at room temperature 10 minutes untilstarting material consumed. Diluted with dichloromethane, washed withwashed with 1M HCl solution, saturated brine, concentrated to givecrude. Dissolved in 1.5 mL dichloromethane, added catalyticdimethylaminopyridine, triethylamine (0.139 mL, 1 mmol) and cooled to 0°C. To this was added triphosgene (0.1 g, 0.339 mmol) and stirred 40minutes. BOC-aminopiperidine (0.135 g, 0.678 mmol) was then added andstirred at room temperature for 10 minutes. Diluted withdichloromethane, washed with 1M HCl, brine, concentrated volatiles togive crude. Chromatographed (10% to 50% ethylacetale/hexanes) to giveproduct 129 (0.072 g, 0.097 mmol, 59%.) ¹H NMR (CDCl₃) δ 9.04 (dd, 1H),8.07 (d, 1H), 8.04 (s, 1H), 7.74 (d, 4H), 7.50 (dd, 1H), 7.27 (m, 8H),7.06 (dd, 2H), 4.80 (s, 2H), 4.48 (br s, 1H), 4.28 (m, 1H), 4.21 (s,3H), 3.71 (br s, 2H), 3.21 (dd, 2H), 3.03 (dd, 2H), 1.48 (s, 9H.) MS:717 M+1)

Example 130

Carbamate 129 (0.07 g, 0.097 mmol) was dissolved in 2 mL ofdichloromethane. To this was added 0.5 mL of triethylsilane and 0.2 mLof trifluoroacetic acid. Stirred at room temperature and after tenminutes complete by TLC. Concentrated off volatiles, azeotroped withtoluene to give crude. Then dissolved in 1.5 mL dichloromethane, 1.5 mltrifluoroacetic acid. Stirred at room temperature for one hour.Concentrated off volatiles, azeotroped with toluene to give crude.Triturated twice with 1:1 diethylether/hexanes to give product 130(0.0329 g, 0.058 mmol, 60%.) ¹H NMR (CD₃SOCD₃) δ 8.98 (s, 1H), 8.22 (d,1H), 7.95 (s, 2H), 7.74 (dd, 1H), 7.35 (dd, 2H), 7.19 (dd, 2H), 4.70 (s,2H), 4.35 (s, 3H), 4.00 (br s, 1H), 3.44 (br s, 7H.) ¹⁹F NMR: −74.1 MS:451 (M+1), 449 (M−1)

Example 131

Triphosgene (0.06 g, 0.2032 mmol) was added to 0.5 mL dichloromethaneand cooled to 0° C. To this was slowly added glycine tertiary-butylester HCl salt (0.034 g, 0.2032 mmol) and triethylamine (0.14 mL, 1mmol) and stirred at 0° C. Stirred thirty minutes until startingmaterial consumed. Simultaneously, in a separate flasktrimethylsilylethyl ether compound 44 was dissolved in 0.5 mLtetrahydrofuran. To this was added triethylamine (0.028 mL, 0.2032 mmol)and 1M tetrabutylammonium fluoride in tetrahydrofuran (0.1016 mL, 0.1016mmol) and stirred at room temperature. After 20 minutes, diluted withdichoromethane, washed with 1M HCl solution and brine, concentrated togive crude. At 0° C., crude dissolved in 0.5 mL dichloromethane andadded to the glycine isocyanate prepared in situ above. Stirred at 0° C.for 5 minutes, then stirred for one hour at room temperature. Dilutedwith dichloromethane, washed with 1 M HCl solution, brine, concentratedto give crude. Chromatographed (10% to 40% ethylacetate/hexanes) to giveproduct 131 (0.017 g, 0.026 mmol, 52%.) ¹H NMR (CDCl₃) δ 9.03 (d, 1H),8.20 (dd, 1H), 8.05 (s, 1H), 7.75 (d, 4H), 7.51 (dd, 1H), 7.27 (m, 8H),7.04 (dd, 2H), 5.66 (s, 1H), 4.79 (s, 2H), 4.23 (s, 2H), 3.93 (d, 2H),1.5 (s, 9H.) MS: 648 (M+1)

Example 132

Carbamate 131 (0.017 g, 0.026 mmol) was dissolved in 0.5 mL ofdichloromethane. To this was added 0.2 mL of triethylsilane and 0.1 mLof trifluoroacetic acid. Stirred at room temperature and after tenminutes complete by TLC. Concentrated off volatiles, azeotroped withtoluene to give crude. Then dissolved in 0.5 mL dichloromethane, 0.2 mLtriethylsilane, 0.2 ml trifluoroacetic acid. Stirred at room temperaturefor three hours. Concentrated off volatiles, azeotroped with toluene togive crude. Triturated with 1:1 diethylether/hexanes to give product 132(0.0088 gm, 0.021 mmol, 80%.) ¹H NMR (CD₃SOCD₃) δ 8.97 (s, 1H), 8.40 (s,1H), 8.30 (d, 1H), 7.74 (dd, 1H), 7.37 (m, 2H), 7.23 (m, 2H), 4.69 (s,2H0, 4.32 (s, 2H), 3.76 (d, 2H.) ¹⁹F NMR: −74.3 MS: 426 (M+1), 424 (M−1)

Example 133

Carbamate 120 (0.019 g, 0.0435 mmol) was dissolved in 0.5 mL ofdichloroethane. To this was added triethylamine (0.072 mL, 0.52 mmol)and triisopropylsilyl chloride (0.058 mL, 0.26 mmol) and stirred at 50°C. After 19 hours, starting material consumed, diluted withdichloromethane, washed with 1M HCl solution, brine and concentrated togive crude. Chromatographed to give product 133 (0.012 g, 0.0203 mmol,47%.) ¹H NMR (CDCl₃) δ 8.86 (s, 1H), 8.06 (d, 1H), 7.54 (dd, 1H), 7.33(dd, 2H), 7.08 (dd, 2H), 4.78 (s, 2H), 4.21 (s, 4H), 4.01 (br s, 2H),3.35 (br s, 4H), 11.58 (m, 1H), 1.16 (d, 18H.) MS: 593 (M+1)

Example 134

Piperazine carbamate 133 (0.012 g, 0.0203 mmol) was dissolved 0.5 mL ofacetonitrile and 0.2 mL dichloromethane. To this was added Cs₂CO₃(0.0325 g, 0.1 mmol) and 2-bromoacetamide (0.009 g, 0.0608 mmol.)Stirred at room temperature for 3.5 days, until starting material wasconsumed. Diluted with dichloromethane, washed with saturated NH₄Clsolution, concentrated to give product 134 (0.0037 g, 0.0057, 28%.) ¹HNMR (CDCl₃) δ 8.87 (dd, 1H), 8.11 (d, 1H), 7.73 (s, 1H), 7.53 (dd, 1H),7.34 (dd, 2H), 7.07 (dd, 2H), 4.78 (s, 2H), 4.23 (s, 2H), 3.84 (br s,2H), 3.64 (br s, 2H), 3.14 (s, 2H), 2.62 (br s, 4H), 1.58 (m, 3H), 1.17(d, 18H.) MS: 650 (M+1)

Example 135

Mono-carbamate 134 (0.0037 g, 0.0057 mmol) was dissolved in 0.2 mL ofdichloromethane. To this was added trifluoroacetic acid (0.009 mL, 0.114mmol) and stirred at room temperature. After twenty hours, concentratedoff volatiles, azeotroped with toluene (2×), concentrated to give crude.Triturate with 1:1 diethylether/hexanes to give product 135 (0.0015 g,0.0024 mmol, 43%.) ¹H NMR (CD₃OD) δ 8.96 (s, 1H), 8.38 (s, 1H), 7.75 (m,2H), 7.39 (dd, 2H), 7.11 (dd, 2H), 4.87 (s, 2H), 4.42 (s, 2H), 4.0 (brm, 8H), 3.3 (s, 2H.) ¹⁹F: −77.73 MS: 494 (M+1), 492 (M−1)

Example 136

Piperazine carbamate 133 (0.033 g, 0.056 mmol) was dissolved in 0.5 mLdichloromethane. To this was added catalytic dimethylaminopyridine,triethylamine (0.031 mL, 0.225 mmol) and methanesulfonyl chloride(0.0087 mL, 0.112 mmol) at 0° C. After five minutes, continued stirringat room temperature. After one hour starting material consumed. Dilutedwith dichloromethane, washed with saturated NH₄Cl solution, dried(Na₂SO₄) concentrated to give crude. Chromatographed (10% to 60%ethylacetate/hexanes) to give product 136 (0.013 g, 0.019 mmol, 35%.) ¹HNMR (CDCl₃) δ 8.88 (dd, 1H), 8.08 (d, 1H), 7.53 (dd, 1H), 7.33 (dd, 2H),7.05 (dd, 2H), 4.79 (s, 2H), 4.23 (s, 2H), 3.93 (br s, 2H), 3.72 (br s,2H), 3.37 (br s, 4H), 2.88 (s, 3H), 1.58 (m, 3H), 1.17 (d, 18H.) MS: 671(M+1)

Example 137

Mono-carbamate 136 (0.013 g, 0.019 mmol) was dissolved in 0.5 mL ofdichloromethane. To this was added trifluoroacetic acid (0.056 mL, 0.72mmol) and stirred at room temperature. After twenty hours, concentratedoff volatiles, azeotroped with toluene (2×), concentrated to give crude.Triturate with 1:1 diethylether/hexanes to give product 137 (0.0066 g,0.013 mmol, 68%.) ¹H NMR (CDCl₃) δ 9.01 (s, 1H), 8.17 (s, 1H), 7.61 (s,1H), 7.27 (dd, 2H), 7.07 (dd, 2H), 4.79 (s, 2H), 4.37 (s, 2H), 3.93 (brs, 2H), 3.72 (br s, 2H), 3.39 (br s, 4H), 2.89 (s, 3H.) MS: 515 (M+1),513 (M−1)

Example 138

Piperazine carbamate 133 (0.033 g, 0.056 mmol) was dissolved in 0.5 mLdichloromethane. To this was added catalytic dimethylaminopyridine,triethylamine (0.031 mL, 0.225 mol) and methanesulfonyl chloride (0.0087mL, 0.112 mmol) at 0° C. After five minutes, continued stirring at roomtemperature. After one hour starting material consumed. Diluted withdichloromethane, washed with saturated NH₄Cl solution, dried Na₂SO₄)concentrated to give crude. Chromatographed (10% to 50%ethylacetate/hexanes) to giveproduct 138 (0.012 g, 0.017 mmol, 31%.) ¹HNMR (CDCl₃) δ 8.87 (dd, 1H), 8.09 (d, 1H), 7.53 (dd, 1H), 7.31 (dd, 2H),7.07 (dd, 2H), 4.79 (s, 2H), 4.23 (s, 2H), 3.87 (br s, 2H), 3.66 (br s,2H), 3.35 (br s, 4H), 2.89 (s, 6H), 1.56 (m, 3H), 1.17 (d, 18H.) MS: 700(M+1)

Example 139

Mono-carbamate 138 (0.012 g, 0.017 mmol) was dissolved in 0.5 mL ofdichloromethane. To this was added trifluoroacetic acid (0.056 mL, 0.72mmol) and stirred at room temperature. After twenty hours, concentratedoff volatiles, azeotroped with toluene (2×), concentrated to give crude.Triturate with 1:1 diethylether/hexanes to give product 139 (0.0039 g,0.007 mmol, 42%.) ¹H NMR (CDCl₃) δ 9.00 (s, 1H), 8.18 (d, 1H), 7.60 (s,1H), 7.27 (dd, 2H), 7.07 (dd, 2H), 4.78 (s, 2H), 4.36 (s, 2H), 3.88 (brs, 2H), 3.67 (br s, 2H), 3.35 (br s, 4H), 2.89 (s, 6H.) MS: 544 (M+1),542 (M−1)

Example 140

Piperazine carbamate 133 (0.033 g, 0.056 m-mol) was dissolved in 0.5 mLdichloromethane. To this was added catalytic dimethylaminopyridine,triethylamine (0.031 mL, 0.225 mmol) and methanesulfonyl chloride(0.0087 mL, 0.112 mmol) at 0° C. After five minutes, continued stirringat room temperature. After one hour starting material consumed. Dilutedwith dichloromethane, washed with saturated NH₄Cl solution, dried(Na₂SO₄) concentrated to give crude. Chromatographed (50% to 100%ethylacetate/hexanes) to give product 140 (0.012 g, 0.018 mmol, 32%.) ¹HNMR (CDCl₃) δ 8.85 (dd, 1H), 8.11 (d, 1H), 7.52 (dd, 1H), 7.31 (dd, 2H),7.07 (dd, 2H), 4.79 (s, 2H), 4.23 (s, 2H), 3.82 (br s, 2H), 3.60 (br s,2H), 3.34 (br s, 4H), 2.91 (s, 6H), 1.56 (m, 3H), 1.17 (d, 18H.) MS: 664(M+1)

Example 141

Mono-carbamate 140 (0.012 gm, 0.018 mmol) was dissolved in 0.5 mL ofdichloromethane. To this was added trifluoroacetic acid (0.056 mL, 0.72mmol) and stirred at room temperature. After twenty hours, concentratedoff volatiles, azeotroped with toluene (2×), concentrated to give crude.Triturate with 1:1 diethylether/hexanes to give product 141 (0.0051 g,0.0083 mmol, 46%.) ¹H NMR (CDCl₃) δ 9.00 (s, 1H), 8.21 (s, 1H), 7.60 (s,1H), 7.27 (dd, 2H), 7.07 (dd, 2H), 4.76 (s, 2H), 4.37 (s, 2H), 3.83 (brs, 2H), 3.61 (br s, 2H), 3.35 (br s, 4H), 2.92 (s, 6H.) ¹⁹F: -76.3 MS:508 (M+1), 506 (M−1)

Example 142

Trimethylsilylethyl ether 44 (0.03 g, 0.0508 mmol) was dissolved in 0.5mL dry tetrahydrofuran. To this was added triethylamine (0.028 mL,0.2032 mmol) and 1 M tetrabutylammonium fluoride solution intetrahydrofuran (0.1016 mL, 0.1016 mmol.) Stirred at room temperature 10minutes until starting material consumed. Diluted with dichloromethane,washed with washed with 1M HCl solution, saturated brine, dried(Na₂SO₄,) concentrated to give crude. Dissolved in 0.5 mLdichloromethane, added catalytic dimethylaminopyridine, triethylamine(0.08 mL, 0.6 mmol) and cooled to 0° C. To this was added triphosgene(0.03 g, 0.1016 mmol) and stirred 30 minutes. Azetid-3-yl carbamic acidt-butyl ester (0.035 g, 0.2032 mmol) and triethylamine (0.08 mL, 0.6mmol) was then added and stirred at room temperature for 50 minutes.Diluted with dichloromethane, washed with 1M HCl, brine, dried (Na₂SO₄,)concentrated volatiles to give crude. Chromatographed (10% to 50%ethylacetate/lexanes) to give product 142 (0.024 g, 0.035 mmol, 69%.) ¹HNMR (CDCl₃) δ 9.04 (dd, 1H), 8.17 (d, 1H), 8.03 (s, 1H), 7.74 (d, 4H),7.51 (dd, 1H), 7.27 (m, 8H), 7.08 (dd, 2H), 5.00 (m, 1H), 4.80 (s, 2H),4.52 (m, 2H), 4.23 (s, 2H), 3.91 (m, 2H), 1.48 (s, 9H.) MS: 689 (M+1)

Example 143

Carbamate 142 (0.024 g, 0.035 mmol) was dissolved in 0.5 mL ofdichloromethane. To this was added 0.4 mL of triethylsilane and 0.2 mLof trifluoroacetic acid. Stirred at room temperature and after tenminutes complete by TLC. Concentrated off volatiles, azeotroped withtoluene to give crude. Then dissolved in 0.75 mL dichloromethane, 0.75ml trifluoroacetic acid. Stirred at room temperature for one hour.Concentrated off volatiles, azeotroped with toluene to give crude.Triturated twice with 1:1 diethylether/hexanes to give product 143(0.0128 g, 0.024 mmol, 68%.) ¹H NMR (CD₃SOCD₃) δ 9.00 (s, 1H), 8.38 (brs, 3H), 7.75 (s, 1H), 7.36 (br s, 2H), 7.22 (br s, 2H), 4.72 (s, 2H),4.32 (br m, 5H), 3.14 (br s, 2H.) ¹⁹F NMR: −74.0 MS: 423 (M+1), 421(M−1)

Example 144

To crude triflate 7 (0.025 g, 0.048 mmol) in 1 mL of dichloroethane wasadded triethylamine (0.014 mL, 0.096 mmol) and benzenethiol (0.008 ml,0.072 mmol) and the solution stirred at room temperature. After 15 hrs,the mixture was concentrated and chromatographed on silica gel elutingwith EtOAc/hexanes to give compound 144 (0.01 g, 44%) as a yellow oil.¹H NMR (CDCl₃) δ 9.2 (m, 2H), 7.6 (dd, 1H), 7.06 (m, 5H), 7.0 (t, 2 H),5.97 (s, 2H), 4.85 (s, 2H), 3.72 (s, 3H); MS: 474 (M+1)

Example 145

MOM ether 144 (0.009 g, 0.019 mmol) in 1 mL of dichloromethane wastreated with TFA (0.015 mL, 0.19 mmol) at room temperature for 15 hrs.The volatiles were removed in vacuo and the residue was triturated withdiethylether to afford7-(4-fluoro-benzyl)-9-hydroxy-5-phenylsulfanyl-pyrrolo[3,4-g]quinoline-6,8-dione145 as a yellow solid. ¹H NMR (CDCl₃) δ 9.31 (d, 2H), 7.81 (m, 1H), 7.46(dd, 2H), 7.17 (m, 5H), 7.04 (t, 2 H), 5.97 (s, 2H), 4.88 (s, 2H); MS:430 (M+1).

Example 146

To the triflate 5 (0.045 g, 0.07 mmol) in toluene (0.7 mL)/ethanol (0.3mL)/water (0.2 mL) were added potassium carbonate (0.037 g, 0.175 mmol),trans-phenylvinylbronic acid (0.016 g, 0.105 mmol) and tetrakis(triphenylphosphine)-palladium (0) (0.012 g, 0.011 mmol). The mixture inthe flask was flushed with argon three times. It was heated to 120° C.under argon for 3 hours. Cooling to room temperature, it was dilutedwith EtOAc and washed with 1N HCl, saturated NaHCO3 and brine. Theorganic phase was dried (MgSO₄) and concentrated. The residue waschromatographed on a silica gel column, eluting with EtOAc/Hexane toafford the product 146 (0.031 g, 75%). MS: 613 (M+Na).

Example 147

Compound 146 (8 mg, 0.013 mmol) was dissolved in dichloromethane (1 mL)at room temperature under nitrogen. Triethylsilane (0.034 mL) was addedfollowed by TFA (0.02 mL) slowly. The mixture was stirred at roomtemperature for 30 min. The solvent was removed at reduced pressure. Thecrude product was triturated in diethylether/hexane to afford a yellowsolid7-(4-fluoro-benzyl)-9-hydroxy-5-styryl-pyrrolo[3,4-g]quinoline-6,8-dione147 (0.005 g, 88%. ¹H NMR (CDCl₃): δ 8.99 (d, 1H), 8.88 (d, 1H), 8.05(d, 1H), 7.67 (m, 3H), 7.36-7.52 (m, 5H), 7.01 (m, 3H), 4.87 (s, 2H);MS: 425 (M+1).

Example 148

To a solution of trifluoromethanesulfonic acid diethoxyphosphorylmethylester (D. P. Phillion, et al, Tetra. Lett., 27 (1986) 1477-1480, 0.040g, 0.104 mmol) dissolved in acetonitrile (0.75 mL) was added the phenol6 (0.044 g, 0.146 mmol) and CsCO₃ (0.102 g, 0.314 mmol). The reactionmixture was stirred at room temperature for 3 hours under an inertatmosphere then filtered and concentrated in vacuo. The residue waspurified by silica gel chromatography (3/1—ethylacetate/hexane) toafford the product 148 (0.014 g, 25%) as a solid: ¹H NMR (CDCl₃) δ 9.1(d, 1H), 8.9 (d, 1H), 7.6 (dd, 1H), 7.5 (dd, 2H), 7.0 (t, 2H), 5.8 (s,2H), 5.0 (d, 2H), 4.8 (s, 2H), 4.2 (m, 4H), 3.7 (s, 3H), 1.3 (t, 6H);³¹P NMR (CDCl₃) δ 19.0; MS: 533 (M+1).

Example 149

A solution of the phosphonate 148 (0.014 g, 0.026 mmol) indichloromethane (0.96 mL) was treated with trifluoroacetic acid (0.020mL, 0.260 mmol). The reaction mixture was stirred at room temperatureunder an inert atmosphere for 3 hours. The volatiles were removed invacuo with toluene. The solid was triturated in diethylether/hexane toafford the product 149 (0.11 g, 86%) as a TFA salt: ¹H NMR (CDCl₃) δ 9.0(d, 1H), 8.9 (d, 1H), 7.7 (dd, 1H), 7.5 (dd, 2H), 7.0 (t, 2H), 5.0 (d,2H), 4.9 (s, 2H), 4.2 (m, 4H), 1.3 (s, 6H); ³¹P NMR (CDCl₃) δ 19.2; MS:489 (M+1), 487 (M−1).

Example 150

Dibenzyl hydroxymethyl phosphonate triflate was prepared from dibenzylhydroxymethyl phosphonate (M. Krecmerova, et al, Czech. Chem. Commun.,55, 1990, 2521-2536) by the method of: Y. Xu, et al, J. Org. Chem., 61(1996) 7697-7701. To a solution of dibenzyl hydroxymethyl phosphonatetriflate (0.050 g, 0.131 mmol) dissolved in acetonitrile (1.87 mL) wasadded the phenol 6 (0.078 g, 0.183 mmol) and CsCO₃ (0.102 g, 0.314mmol). The reaction mixture was stirred at room temperature for 3 hoursunder an inert atmosphere then filtered and concentrated in vacuo. Theresidue was purified by silica gel chromatography(1/1—ethylacetate/hexane) to afford the product 150 (0.030 g, 35%) as asolid: ¹H NMR (CDCl₃) δ 9.0 (d, 1H), 8.65 (d, 1H), 7.5 (dd, 2H), 7.4(dd, 1H), 7.3 (m, 10H), 7.0 (t, 2H), 5.8 (s, 2H), 5.1 (m, 4H), 4.9 (d,2H), 4.8 (s, 2H), 3.7 (s, 3H); ³¹P NMR (CDCl₃) δ 20.1; MS: 657 (M+1).

Example 151

A solution of the phosphonate 150 (0.029 g, 0.044 mmol) indichloromethane (1.6 mL) was treated with trifluoroacetic acid (0.034mL, 0.44 mmol). The reaction mixture was stirred at room temperatureunder an inert atmosphere for 3 hours. The volatiles were removed invacuo with toluene. The solid was triturated in diethylether/hexane toafford the product 151 (0.024 g, 89%) as a TFA salt: ¹H NMR (CDCl₃) δ8.9 (d, 1H), 8.6 (d, 1H), 7.5 (dd, 2H), 7.45 (dd, 1H), 7.3-7.2 (m, 10H),7.0 (t, 2H), 5.1-5.0 (m, 4H), 5.0 (d, 2H), 4.8 (s, 2H); ³¹P NMR (CDCl₃)δ 20.3; MS: 613 (M−1), 611 (M−1).

Example 152

To a solution of diallyl hydroxymethyl phosphonate triflate (prepared bya method similar to: D. P. Phillion, et al, Tetra. Lett., 27 (1986)1477-1480 and Y. Xu, et al, J. Org. Chem., 61 (1996) 7697-7701, 0.153 g,0.471 mmol) dissolved in acetonitrile (6.7 mL) was added7-(4-fluoro-benzyl)-5-hydroxy-9-methoxymethoxy-pyrrolo[3,4-g]quinoline-6,8-dione6 (0.060 g, 0.157 mmol) and CsCO₃ (0.154 g, 0.471 mmol). The reactionmixture was stirred at room temperature for 2 hours under an inertatmosphere ten filtered and concentrated in vacuo. The residue waspurified by silica gel chromatography (3/1—ethylacetate/hexane) toafford[7-(4-fluoro-benzyl)-9-methoxymethoxy-6,8-dioxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-5-yloxymethyl]-phosphonicacid diallyl ester 152 (0.051 g, 59%) as a solid: ¹H NMR (CDCl₃) δ 9.05(d, 1H), 8.85 (d, 1H), 7.6 (dd, 1H), 7.45 (dd, 2H), 7.0 (t, 2H), 5.9 (m,2H), 5.8 (s, 2H), 5.3 (d, 2H), 5.2 (d, 2H), 5.0 (d, 2H), 4.8 (s, 2H),4.6 (m, 4H), 3.7 (s, 3H); ³¹P NMR (CDCl₃) δ 19.9; MS: 557 (M+1).

Example 153

A solution of the phosphonate 152 (0.0065 g, 0.0117 mmol) indichloromethane (0.425 mL) was treated with trifluoroacetic acid (0.009mL, 0.117 mmol). The reaction mixture was stirred at room temperatureunder an inert atmosphere for 1 hour. The volatiles were removed invacuo with toluene. The solid was triturated in diethylether/hexane toafford the product 153 (0.006 g, 100%) as a TFA salt: ¹H MR (CDCl₃) δ9.0 (d, 1H), 8.9 (d, 1H), 7.7 (dd, 2H), 7.5 (dd, 1H), 7.0 (t, 2H), 5.9(m, 2H), 5.3 (d, 2H), 5.2 (d, 2H), 5.0 (d, 2H), 4.85 (s, 2H), 4.6 (m,4H); ³¹P NMR (CDCl₃) δ 20.0; MS: 513 (M+1), 511 (M−1).

Example 154

Diethyl hydroxymethyl phosphonate triflate was prepared from diethylhydroxymethyl phosphonate (Aldrich, St. Louis, Mo.,) by the method of:D. P. Phillion, et al, Tetra. Lett., 27, 1986, 1477-1480. To a solutionof diethyl hydroxymethyl phosphonate triflate (0.61 g, 0.202 mmol)dissolved in acetonitrile (2.9 mL) was added the phenol 12 (0.100 g,0.202 mmol) and CsCO₃ (0.198 g, 0.607 mmol). The reaction mixture wasstirred at room temperature for 3 hours under an inert atmosphere thenfiltered and concentrated in vacuo. The residue was purified by silicagel chromatography (1/1—ethylacetate/hexane) to afford the product 154(0.130 g, 100%) as a solid. ¹H NMR (CDCl₃) δ 8.95 (d, 1H), 8.9 (d, 1H),7.6 (dd, 1H), 7.5 (dd, 2H), 7.0 (t, 2H), 4.9 (d, 2H), 4.8 (s, 2H), 4.2(m, 4H), 1.5 (m, 3H), 1.3 (t, 6H), 1.2 (d, 18H); ³¹P NMR (CDCl₃) δ 19.5;MS: 645 (M+1).

Example 155

A solution of the phosphonate 154 (0.020 g, 0.031 mmol) indichloromethane (0.311 mL) was treated with trimethylsilane bromide(0.0246 mL, 0.186 mmol). The reaction mixture was stirred at roomtemperature overnight under an inert atmosphere. The volatiles wereremoved in vacuo with methanol. The solid was washed withdichloromethane to afford the diacid 155 (0.010 g, 77%): ¹H NMR (CD₃OD)δ 9.5 (d, 1H), 9.2 (d, 1H), 8.2 (dd, 1H), 7.5 (dd, 2H), 7.1 (t, 2H), 5.0(d, 2H), 4.9 (s, 2H); ³¹P NMR (CD₃OD) δ 16.2; MS: 433 (M+1), 431 (M−1).

Example 156

To a solution of the phosphonate 154 (0.038 g, 0.059 mmol) dissolved indichloromethane (0.297 mL) and ethanol (0.297 mL) was added sodiumborohydride (0.475 mL, 0.237 mmol). The reaction mixture stirred at roomtemperature overnight under an inert atmosphere and then wasconcentrated in vacuo. The residue was dissolved in ethylacetate andwashed with saturated NH₄Cl and brine. The organic phase was dried(MgSO₄) then concentrated in vacuo. The residue was purified by silicagel chromatography (1/99—methanol/dichloromethane) to afford the product156 (0.022 g, 59%): ¹H NMR (CDCl₃) δ 8.9 (d, 1H), 8.4 (d, 1H), 7.5 (dd,1H), 7.4 (dd, 2H), 7.0 (t, 2H), 6.0 (s, 1H), 5.8 (bs, 1H), 5.2 (d, 1H),4.6-4.4 (m, 2H), 4.4 (d, 1H), 4.3-4.2 (m, 4H), 1.6 (m, 3H), 1.4 (m, 6H),1.15 (d, 18H); ³¹P NMR (CDCl₃) δ 20.95; MS: 647 (M+1).

Example 157

A solution of the phosphonate 156 (0.025 g, 0.039 mmol) indichloromethane (1.41 mL) was treated with trifluoroacetic acid (0.030mL, 0.390 mmol). The reaction mixture was stirred at room temperatureunder an inert atmosphere overnight. The volatiles were removed invacuo, azeotroping to dryness with toluene. The solid was triturated indiethylether/hexane to afford the product 157 (0.021 g, 100%) as a TFAsalt: ¹H NMR (CDCl₃) δ 9.0 (d, 1H), 8.6 (d, 1H), 7.6 (dd, 1H), 7.4 (dd,2H), 7.0 (t, 2H), 6.2 (bs, 1H), 6.0 (s, 1H), 5.1 (d, 1H), 4.7-4.5 (m,2H), 4.5 (d, 1H), 4.25 (m, 4H), 1.4 (m, 6H); ³¹P NMR (CDCl₃) δ 20.1; MS:491 (M+1), 489 (M−1).

Example 158

A solution of phosphonate 157 (0.0185 g, 0.0378 mmol) in dichloromethane(0.455 mL) was cooled to 0° C. Triethylsilane (0.0603 mL, 0.378 mmol)and then trimethylsilane triflate (0.0205 mL, 0.113 mmol) were added.The reaction stirred for 15 minutes under an inert atmosphere. Themixture was partitioned between dichloromethane and water. The organicphase was washed with saturated NaHCO₃ then dried (MgSO₄) andconcentrated in vacuo. The solid was triturated in diethylether/hexaneto afford the product 158 (0.015 g, 84%): ¹H NMR (CDCl₃) δ 9.0 (dd, 1H),8.6 (dd, 1H), 7.6 (dd, 1H), 7.35 (dd, 2H), 7.15 (t, 2H), 4.8 (s, 2H),4.5 (s, 2H), 4.3 (d, 2H), 4.2 (m, 4H), 1.3 (t, 6H); ³¹P NMR (CDCl₃) δ18.7; MS: 475 (M+1).

Example 159

To a solution of phenol 6 (0.063 g, 0.165 mmol) dissolved in THF (0.86mL) was added dimethyl hydroxyethyl phosphonate (0.076 g, 0.495 mmol),triphenylphosphine (0.108 g, 0.412 mmol), and diethyl azodicarboxylate(0.039 mL, 0.247 mmol). The reaction mixture stirred at room temperatureunder an inert atmosphere overnight. The residue was purified directlyby silica gel chromatography (5/95—methanol/ethylacetate) to afford theproduct 159 (0.022 g, 26%): ¹H NMR (CDCl₃) δ 9.05 (d, 1H), 8.9 (d, 1H),7.6 (dd, 1H), 7.5 (dd, 2H), 7.0 (t, 2H), 5.8 (s, 2H), 4.8 (d, 2H), 4.75(m, 2H), 3.8 (d, 6H), 3.7 (s, 3H), 2.5 (m, 2H); ³¹P NMR (CDCl₃) δ 30.2;MS. 519 (M+1).

Example 160

A solution of the phosphonate 159 (0.012 g, 0.024 mmol) indichloromethane (0.863 mL) was treated with trifluoroacetic acid (0.018mL, 0.240 mmol). The reaction mixture was stirred at room temperatureunder an inert atmosphere overnight. The volatiles were removed in vacuowith toluene. The solid was triturated in diethylether/hexane to affordthe product 160 (0.0095 g, 84%) as a TFA salt: ¹H NMR (CDCl₃) δ 9.0 (d,1H), 8.9 (d, 1H), 7.7 (dd, 1H), 7.5 (dd, 2H), 7.0 (t, 2H), 4.85 (d, 2H),4.8 (m, 2H), 3.8 (d, 6H), 2.5 (m, 2H); ³¹P NMR (CDCl₃) δ 30.3; MS: 475(M+1), 473 (M−1).

Example 161

A solution of diethyl phosphonacetic acid (0.700 g, 3.57 mmol) dissolvedin THF was cooled to 0° C. Borane-THF complex (7.14 mL) in 1M THF wasadded dropwise. The reaction mixture was stirred for 3 hours under aninert atmosphere then concentrated in vacuo. The residue was directlypurified by silica gel chromatography (5/95—methanol/ethylacetate) toafford the product, diethyl hydroxyethyl phosphonate, 161 (0.583 g, 90%)as an oil: ¹H NMR (CDCl₃) δ 4.1 (m, 4H), 3.9 (m, 2H), 2.1 (m, 2H), 1.3(t, 6H); ³¹P NMR (CDCl₃) δ 30.4; MS: 183 (M+1).

Example 162

To a solution of phenol 12 (0.023 g, 0.046 mmol) dissolved in THF (0.24mL) was added diethyl hydroxyethyl phosphonate 161 (0.025 g, 0.137mmol), triphenylphosphine (0.030 g, 0.114 mmol), and diethylazodicarboxylate (0.011 mL, 0.069 mmol). The reaction mixture stirred atroom temperature under an inert atmosphere overnight. The residue waspurified directly by silica gel chromatography(75/25—ethylacetate/hexane). The residue was purified again by silicagel chromatography (80/20—toluene/acetone) to afford the product 162(0.032 g, 48%): ¹H NMR (CDCl₃) δ 8.9 (d, 1H), 8.8 (d, 1H), 7.6 (dd, 1H),7.45 (dd, 2H), 7.0 (t, 2H), 4.8 (s, 2H), 4.7 (m, 2H), 4.15 (m, 4H), 2.5(m, 2H), 1.5 (m, 3H), 1.3 (g, 6H), 1.2 (d, 18H); ³¹P NMR (CDCl₃) δ 27.6;MS: 659 (M+1).

Example 163

A solution of the phosphonate 162 (0.012 g, 0.018 mmol) indichloromethane (0.663 mL) was treated with trifluoroacetic acid (0.014mL 0.180 mmol). The reaction mixture was stirred at room temperatureunder an inert atmosphere overnight. The volatiles were removed in vacuowith toluene. The solid was triturated in diethylether/hexane to affordthe product 163 (0.008 g, 89%) as a TFA salt: ¹H NMR (CDCl₃) δ 9.0 (dd,1H), 8.9 (dd, 1H), 7.7 (dd, 1H), 7.5 (dd, 2H), 7.0 (t, 2H), 4.8 (s, 2H),4.75 (m, 2H), 4.15 (m, 4H), 2.45 (m, 2H), 1.3 (t, 6H); ³¹P NMR (CDCl₃) δ27.5; MS: 503 (M+1), 501 (M−1).

Example 164

To a solution of phenol 12 (0.097 g, 0.196 mmol) dissolved in THF (1.02mL) was added (2-hydroxyethyl)-phosphonic acid dimethyl ester (0.091 g,0.589 mmol), triphenylphosphine (0.129 g, 0.491 mmol), and diethylazodicarboxylate (0.046 mL, 0.295 mmol). The reaction mixture stirred atroom temperature under an inert atmosphere overnight. The residue waspurified directly by silica gel chromatography(85/15—ethylacetate/hexane) to afford a mixture of product 164 andtriphenylphosphine oxide (0.160 g): ¹H NMR (CDCl₃) δ 8.95 (d, 1H), 8.75(d, 1H), 7.7-7.4 (m, 12H), 7.0 (t, 2H), 4.8 (s, 2H), 4.7 (m, 2H), 3.8(d, 6H), 2.5 (m, 2H), 1.5 (m, 3H), 1.2 (d, 18H); ³¹P NMR (CDCl₃) δ 30.5(triphenylphosphine oxide), 29.3; MS: 631 (M+1).

Example 165

A solution of the phosphonate 164 (0.025 g, 0.040 mmol) indichloromethane (0.397 mL) was treated with trimethylsilane bromide(0.0314 mL, 0.24 mmol). The reaction mixture was stirred at roomtemperature under an inert atmosphere overnight. The volatiles wereremoved in vacuo with methanol. The solid was washed withdichloromethane to afford the diacid 165 (0.0094 g, 53%): ¹H NMR (CD₃OD)δ 9.4 (dd, 1H), 9.1 (dd, 1H), 8.05 (dd, 1H), 7.5 (dd, 2H), 7.1 (t, 2H),4.9 (s, 21), 4.8 (m, 2H), 2.45 (m, 2H); ³¹P NMR (CD₃OD) δ 24.7; MS: 447(M+1), 445 (M−1).

Example 166

To a solution of allylphosphonic dichloride (4 g, 25.4 mmol) and phenol(5.2 g, 55.3 mmol) in CH₂Cl₂ (40 mL) at 0° C. was added triethylamine(TEA, 8.4 ML, 60 mmol). After stirring at room temperature for 1.5 h,the mixture was diluted with hexane-ethylacetate and washed with HCl(0.3 N) and water. The organic phase was dried over MgSO₄, filtered andconcentrated under reduced pressure. The residue was filtered through apad of silica gel (eluted with 2:1 hexane-ethyl acetate) to afford crudeproduct diphenol allylphosphonate (7.8 g, containing the excessivephenol) as an oil which was used directly without any furtherpurification. The crude material was dissolved in CH₃CN (60 mL), andNaOH (4.4N, 15 mL) was added at 0° C. The resulting mixture was stirredat room temperature for 3 h, then neutralized with acetic acid to pH=8and concentrated under reduced pressure to remove most of theacetonitrile. The residue was dissolved in water (50 mL) and washed withCH₂Cl₂ (three 25 mL portions). The aqueous phase was acidified withconcentrated HCl at 0° C. and extracted with ethyl acetate. The organicphase was dried over MgSO₄, filtered, evaporated and co-evaporated withtoluene under reduced pressure to yield desired monophenolallylphosphonate (4.75 g. 95%) as an oil.

To a solution of monophenol allylphosphonate (4.75 g, 24 mmol) intoluene (30 mL) was added SOCl₂ (5 mL, 68 mmol) and DMF (0.05 mL). Afterstirring at 65° C. for 4 h, the reaction was complete as shown by ³¹PNMR. The reaction mixture was evaporated and co-evaporated with tolueneunder reduced pressure to give the mono chloride (5.5 g) as an oil. To asolution of the mono chloride in CH₂Cl₂ (25 mL) at 0° C. was added ethyl(S)-lactate (3.3 mL, 28.8 mmol), followed by TEA. The mixture wasstirred at 0° C. for 5 min, then at room temperature for 1 h, andconcentrated under reduced pressure. The residue was partitioned betweenethylacetate and HCl (0.2N), the organic phase was washed with water,dried over MgSO₄, filtered and concentrated under reduced pressure. Theresidue was purified by chromatography on silica gel to afford the allylmonolactate (5.75 g, 80%) as an oil (2:1 mixture of two isomers): ¹H NMR(CDCl₃) δ 7.1-7.4 (m, 5H), 5.9 (m, 1H), 5.3 (m, 2H), 5.0 (m, 1H), 4.2(m, 2H), 2.9 (m, 2H), 1.6; 1.4 (d, 3H), 1.25 (m, 3H); ³¹P NMR (CDCl₃) δ25.4, 23.9.

A solution of the ally) monolactate (2.5 g, 8.38 mmol) in CH₁₂Cl₂ (30mL) was bubbled with ozone air at −78° C. until the solution becameblue, then bubbled with nitrogen until the blue color disappeared.Methyl sulfide (3 mL) was added at −78° C. The mixture was warmed up toroom temperature, stirred for 16 h and concentrated under reducedpressure to give desired aldehyde 166 (3.2 g, as a 1:1 mixture of DMSO):¹H NMR (CDCl₃) δ 9.8 (m, 1H), 7.1-7.4 (m, 5H), 5.0 (m, 1H), 4.2 (m, 2H),3.4 (m, 2H), 1.6; 1.4 (d, 3H), 1.25 (m, 3H). ³¹P NMR (CDCl₃) δ 17.7,15.4.

Example 167

To a solution of 2-[(2-oxo-ethyl)-phenoxy-phosphinoyloxy]-propionic acidethyl ester; aldehyde 166 (0.082 g, 0.218 mmol) in a 1: mixture of DMSOand 1,2-dichloroethane was added acetic acid (0.050 mL, 0.870 mmol) thensodium cyanoborohydride (0.027 g, 0.435 mmol). The reaction mixturestirred at room temperature for three hours under an inert atmosphere.Saturated NaHCO₃ was added to the reaction mixture and was stirred forfive more minutes. The mixture was concentrated in vacuo to remove mostof the dichloroethane. Brine was added and then the crude product wasextracted into ethylacetate. The organic phase was dried (MgSO₄) andconcentrated. The residue was purified by silica gel chromatography(5/95—methanol/dichloromethane) to afford the product 167 (0.047 g,73%), an oil as a mixture of two diastereomers: ¹H NMR (CDCl₃) δ 7.1-7.4(m, 5H), 5.1 (m, 1H), 4.25 (m, 2H), 4.1 (m, 2H), 2.3 (m, 4H), 1.6 & 1.4(d, 3H), 1.25 (m, 3H); ³¹P NMR (CDCl₃) δ 29.0, 26.8.

Example 168

To a solution of phenol 40 (0.033 g, 0.065 mmol) dissolved in THF (0.34mL) was added ethyl-lactate phosphonate alcohol 167 (0.029 g, 0.097mmol), triphenylphosphine (0.043 g, 0.162 mmol), and diethylazodicarboxylate (0.015 mL, 0.097 mmol). The reaction mixture stirred atroom temperature under an inert atmosphere overnight. The residue waspurified directly by silica gel chromatography(50/50—ethylacetate/hexane) to afford the product 168 (0.027 g, 53%).Separation of the diastereomers by chromatography allowed forcharacterization of 168a (0.016 g): ¹H NMR (CDCl₃) δ 9.1 (dd, 1H), 8.8(dd, 1H), 7.9 (s, 1H), 7.6 (m, 4H), 7.55 (m, 1H), 7.4 (dd, 2H), 7.1-7.4(m, 11H), 7.0 (t, 2H), 5.0 (m, 1H), 4.9 (s, 2H), 4.8 (m, 2H), 4.1 (q,3H), 2.75 (m, 2H), 1.4 (d, 3H), 1.2 (t, 3H); ³¹P NMR (CDCl₃) δ 26.05;MS: 790 (M+1)—and 168b (0.011 g): ¹H NMR (CDCl₃) δ 9.1 (dd, 1H), 8.8(dd, 1H), 7.95 (s, 1H), 7.6 (m, 4H), 7.55 (m, 1H), 7.40 (dd, 2H),7.1-7.4 (m, 11H), 7.05 (t, 2H), 5.05 (m, 1H), 4.85 (s, 2H), 4.8 (m, 2H),4.15 (q, 3H), 2.7 (m, 2H), 1.55 (d, 3H), ³¹P NMR (CDCl₃) δ 24.37; MS:790 (M+1)

Example 169a

A solution of the phosphonate 168a (0.013 g, 0.0165 mmol) indichloromethane (0.5 mL) was treated with trifluoroacetic acid (0.1 mL)and triethylsilane (0.2 mL). The reaction mixture was stirred at roomtemperature under an inert atmosphere for 20 minutes. The volatiles wereremoved in vacuo with toluene. The solid was triturated indiethylether/hexane to afford the product 169a (0.008 g, 80%) as a TFAsalt: ¹H NMR (CDCl₃) δ 8.95 (dd, 1H), 8.9 (dd, 1H), 7.6 (m, 1H), 7.5(dd, 2H), 7.1-7.4 (m, 5H), 7.0 (t, 2H), 5.0 (m, 1H), 5.0 (m, 2H), 4.85(s, 2H), 4.15 (q, 3H), 2.8 (m, 2H), 1.4 (d, 3H), 1.25 (t, 3H); ³¹P NMR(CDCl₃) δ 26.13; MS: 623 (M+1), 621 (M−1).

Example 169b

A solution of the phosphonate 168b (0.011 g, 0.014 mmol) indichloromethane (0.5 mL) was treated with trifluoroacetic acid (0.1 mL)and triethylsilane (0.2 mL). The reaction mixture was stirred at roomtemperature under an inert atmosphere for 20 minutes. The volatiles wereremoved in vacuo with toluene. The solid was triturated indiethylether/hexane to afford the product 169b (0.005 g, 60%) as a TFAsalt: ¹H NMR (CDCl₃) δ 8.95 (dd, 1H), 8.9 (dd, 1H), 7.65 (m, 1H), 7.5(dd, 2H), 7.1-7.4 (m, 5H), 7.0 (t, 2H), 5.1 (m, 2H), 4.9 (m, 1H), 4.85(s, 2H), 4.15(q, 3H), 2.7 (m, 2H), 1.55 (d, 3H), 1.2 (t, 3H); ³¹P NMR(CDCl₃) δ 24.44; MS: 623 (M+1), 621 (M−1).

Example 170

A solution of ethyl-lactate phosphonate 169 (0.021 g, 0.034 mmol) inDMSO (0.675 mL) and phosphate buffer saline (3.38 ml) was heated to 40°C. The reaction mixture was treated with esterase—from porcine liver(0.200 mL) and stirred overnight. Another equivalent of esterase wasadded the following day and the mixture stirred another day. The mixturewas concentrated and purified by reversed phase HPLC to afford theproduct 170 (0.008 g, 46%) as a solid: ¹H NMR (CD₃OD) δ 8.95 (dd, 1H),8.9 (dd, 1H), 7.75 (m, 1H), 7.45 (dd, 2H), 7.05 (t, 2H), 4.9 (s, 2H),4.85 (m, 3H), 2.5 (m, 2H), 1.5 (d, 3H); ³¹P NMR (CD₃OD) δ 26.26; MS: 519(M+1), 517 (M−1).

Example 171

To a solution of phenol 4 (1.14 g, 2.79 mmol) dissolved in dioxane (27.9mL) was added 2-(trimethylsilyl)-ethanol (0.600 mL, 4.18 n-mol),triphenylphosphine (1.46 g, 5.57 mmol), and diethyl azodicarboxylate(0.88 mL, 5.57 mmol). The reaction mixture stirred at room temperatureunder an inert atmosphere overnight. The residue was purified directlyby silica gel chromatography (30/70—ethylacetate/hexane) to afford theproduct 171 (0.240 g, 67%): ¹H NMR (CDCl₃) δ 9.1 (dd, 1H), 8.5 (dd, 1H),7.65 (dd, 1H), 7.45 (dd, 2H), 7.0 (t, 2H), 4.9 (m, 2H), 4.8 (s, 2H),4.45 (q, 2H), 1.5 (t, 3H), 1.4 (m, 2H), 0.1 (s, 9H; MS: 510 (M+1).

Example 172

To the ethyl carbonate 171 (0.716 g, 1.4 mmol) in THF (70.2 mL) wasadded a solution (45 mL) of K₂CO₃ (1.94 g, 14 mmol) in water and4-dimethylaminopyridine (0.035 g, 0.281 mmol). The yellow solution wasstirred at room temperature under an inert atmosphere overnight. Most ofTHF was removed in vacuo and the remaining solution was diluted withdichloromethane, washed with 1N HCl and brine, then dried (MgSO₄) andconcentrated. The crude product was triturated in diethylether/hexane toafford the yellow solid product 172 (0.428 g, 70%): ¹H NMR (CDCl₃) δ 9.1(dd, 1H), 8.65 (dd, 1H), 7.6 (dd, 1H), 7.5 (dd, 2H), 7.0 (t, 2H), 4.85(s, 2H), 4.85 (m, 2H), 1.35 (m, 2H), 0.1 (s, 9H); MS: 438 (M+1).

Example 173

To a solution of (2-benzyloxy-ethyl)-phosphonic acid dibenzyl ester(0.200 g, 0.543 mmol) in THF was added a solution of NaOH (1.36 mL, 1M)in water. The reaction mixture was stirred at room temperature for 3hours. Most of THF was removed in vacuo and the residue was dissolved inwater. The aqueous solution was washed with ethylacetate three timesthen acidified with 1N HCl (to pH=1) then extracted with ethylacetate.The organic phase was dried (MgSO₄), concentrated and co-evaporated withtoluene in vacuo to afford the mono-acid, (2-benzyloxy-ethyl)-phosphonicacid monobenzyl ester, 173 (0.160 g. 100%) as an oil with no furtherpurification: ¹H NMR (CDCl₃) δ 9.25 (bs, 1H), 7.4-7.1 (m, 10OH), 4.5 (s,2H), 3.8 (m, 2H), 2.25 (m, 2H); ³¹P NMR (CDCl₃) δ 28.63.

Example 174

To a solution of the mono-acid 173 (0.160 g, 0.576 mmol) dissolved inacetonitrile (3.84 mL) was added thionyl chloride (0.42 mL, 5.76 mmol).The reaction mixture was heated to 70° C. and stirred for 3 hours atwhich point the reaction was completed as shown by ³¹P NMR (CDCl₃) δ36.7. The reaction mixture was concentrated as such to afford theintermediate mono-chloridate as an oil which was immediately dissolvedin dichloromethane (2.88 mL) and treated with triethylamine (0.321 mL,2.30 mmol). The reaction mixture was cooled to 0° C. and L-alanine ethylester (0.265 g, 1.73 mmol) was added. The mixture was stirred overnightat room temperature under an inert atmosphere and then was concentratedin vacuo. The residue was partitioned between ethylacetate and saturatedNH₄Cl, and the organic phase was washed with brine, dried (MgSO₄) thenconcentrated in vacuo. The residue was purified by chromatography onsilica gel washed with methanol prior to use (1/1—ethylacetate/hexane)to afford the amidate 174 (0.095 g, 45%) as an oil with a 1:1.2 mixtureof diastereomers: ¹H NMR (CDCl₃) δ 7.1-7.4 (m, 10H), 4.6 (s, 2H), 4.1(q, 2H), 3.8 (m, 2H), 3.65 (m, 1H), 2.3 (m, 2H), 1.3 & 1.2 (d, 3H), 1.25(t, 3H); ³¹P NMR (CDCl₃) δ 29.51, 28.70.

Example 175

To a solution of the amidate 174 (0.095 g, 0.243 mmol) dissolved inethanol (4.9 mL) was added palladium (on carbon). The reaction waspurged under a vacuum then submitted to hydrogen gas (via balloonattached to the reaction vessel). After several purges between gas andvacuum the reaction mixture was stirred at room temperature for 4 hours.The mixture was filtered with Celite and concentrated in vacuo to affordthe alcohol 175 (0.74 g, 100%) as an oil with a 1:1.2 mixture ofdiastereomers without further purification: ¹H NMR (CDCl₃) δ 7.4-7.1 (m,5H), 4.15 (m, 2H), 3.7 (q, 2H), 3.5 (m, 1H ), 2.2 (m, 2H), 1.35 & 1.25(d, 3H), 1.25 (m, 3H); ³¹P NMR (CDCl₃) δ 30.82, 30.54.

Example 176

To a solution of phenol 172 (0.073 g, 0.167 mmol) dissolved in THF (1.67mL) was added the alcohol 175 (0.075 g, 0.25 mmol), triphenylphosphine(0.087 g, 0.33 mmol), and diethyl azodicarboxylate (0.042 mL, 0.33mmol). The reaction mixture stirred at room temperature under an inertatmosphere overnight. The residue was purified directly bychromatography on silica gel washed with methanol prior to use(80/20—toluene/acetone) to afford the product 176 (0.065 g, 54%) with a1:1.2 mixture of diastereomers: ¹H NMR (CDCl₃) δ 9.1 (dd, 1H), 8.8 (dd,1H), 7.6 (dd, 1H), 7.5 (dd, 2H), 7.4-7.1 (m, 5H), 7.0 (t, 2H), 4.85 (s,2H), 4.85-4.7 (m, 4H), 4.2 (q, 1H), 4.15 (m, 2H), 4.0-3.8 (m, 1H), 2.65(m, 2H), 1.4 & 1.25 (d, 3H), 1.3 (m, 2H), 1.2 (m, 3H), 0.10 (s, 9H); ³¹PNMR (CDCl₃) δ 27.84, 26.96; MS: 722 (M+1),

Example 177

A solution of the phosphonate 176 (0.030 g, 0.042 mmol) indichloromethane (0.832 mL) was treated with trifluoroacetic acid (0.064mL, 0.84 mmol). The reaction mixture was stirred at room temperatureunder an inert atmosphere for 45 minutes. The volatiles were removed invacuo with toluene. The solid was triturated in diethylether/hexane toafford the product 177 (0.022 g, 85%) as a TFA salt with a 1:1.2 mixtureof diastereomers: ¹H NMR (CDCl₃) δ 9.0 (dd, 1H), 8.85 (dd, 1H), 7.65(dd, 1H), 7.5 (dd, 2H), 7.4-7.1 (m, 5H), 7.0 (t, 2H), 4.85 (s, 2H), 4.85(m, 2H), 4.15 (m, 1H), 4.15 (m, 1H), 4.1 (m, 2H), 3.8 (m, 1H), 2.65 (m,2H), 1.35 & 1.30 (d, 3H), 1.2 (m, 3H); ³¹P NMR (CDCl₃) δ 27.86, 27.05;MS: 622 (M+1), 620 (M−1).

Example 178

A solution of (2-ethoxy-ethyl)-phosphonic acid diethyl ester (0.500 g,2.1 mmol) in ether (8.5 mL) and THF (1.5 mL) was treated with lithiumborohydride. The reaction mixture stirred at room temperature for 1 hourand was then concentrated in vacuo. The crude mixture was partitionedbetween dichloromethane and water. The organic phase was washed withsaturated NaHCO₃ and brine, dried (MgSO4), then concentrated in vacuo.The residue was purified by silica gel chromatography(5/95—methanol/dichloromethane) to afford (3-hydroxy-propyl)-phosphonicacid diethyl ester 178 (0.100 g, 24%) as an oil: ¹H NMR (CDCl₃) δ 4.1(m, 4H), 3.7 (m, 2H), 2.95 (bs, 1H), 1.85 (m, 4H), 1.30 (t, 3H); ³¹P NMR(CDCl₃) δ 33.26; MS: 197 (M+1).

Example 179

To a solution of phenol 40 (0.023 g, 0.046 mmol) dissolved in THF (0.45mL) was added the alcohol 178 (0.013 g, 0.068 mmol), triphenylphosphine(0.024 g, 0.091 mmol), and diethyl azodicarboxylate (0.014 mL, 0.091mmol). The reaction mixture stirred at room temperature under an inertatmosphere overnight. The residue was purified directly by silica gelchromatography (90/10—ethylacetate/hexane) to afford the product 179(0.024 g, 76%): ¹H NMR (CDCl₃) δ 9.1 (dd, 1H), 8.6 (dd, 1H), 7.9 (dd,1H), 7.6 (m, 6H), 7.4 (dd, 2H), 7.2 (m, 6H), 7.0 (t, 2H), 4.8 (s, 2H),4.5 (t, 2H), 4.15 (m, 2H), 2.2 (m, 2H), 2.0 (m, 2H), 1.35 (t, 3H); ³¹PNMR (CDCl₃) δ 31.48; MS: 684 (M+1).

Example 180

A solution of the phosphonate 179 (0.028 g, 0.041 mmol) indichloromethane (0.5 mL) was treated with trifluoroacetic acid (0.1 mL)and triethylsilane (0.2 mL). The reaction mixture was stirred at roomtemperature under an inert atmosphere for 20 minutes. The volatiles wereremoved in vacuo with toluene. The solid was triturated indiethylether/hexane to afford the product 180 (0.020 g, 95%) as a TFAsalt: ¹H NMR (CDCl₃) δ 9.0 (dd, 1H) 8.7 (dd, 1H), 7.65 (dd, 1H), 7.5(dd, 2H), 7.0 (t, 2H), 4.85 (s, 2H), 4.6 (t, 2H), 4.15 (m, 2H), 2.25 (m,2H), 2.05 (m, 2H), 1.35 (t, 3H); ³¹P NMR (CDCl₃) δ 31.45; MS: 517 (M+1))51.6 (M−1).

Example 181

To a solution of 1-BOC-piperazine (0.200 g, 1.08 mmol) in acetonitrile(10.4 mL) was added CsCO₃ (1.05 g, 3.23 mmol) and then cooled to 0° C.Trifluoromethanesulfonic acid diethoxyphosphorylmethyl ester (0.387 g,1.29 mmol) dissolved in acetonitrile (5 mL) was added in a dropwisemanner. The reaction mixture was stirred at room temperature for 1 hourupon which it was concentrated in vacuo. The reaction mixture was takeninto ethylacetate then washed with saturated NH₄Cl and brine, dried(MgSO₄), then concentrated in vacuo. The residue was purified usingsilica gel chromatography (3/97—methanol/dichloromethane) to afford theproduct 181 (0.310 g, 86%) as an oil: ¹H NMR (CDCl₃) δ 4.15 (m, 4H),3.45 (t, 4H), 2.8 (d, 2H), 2.6 (m, 4H), 1.45 (s, 9H), 1.35 (t, 6H); ³¹PNMR (CDCl₃) δ 24.03; MS, 337 (M+1).

Example 182

A solution of the BOC protected piperazine linker phosphonate 181 (0,310g, 0.923 mmol) in dichloromethane (6.15 mL) was treated withtrifluoroacetic acid (0.711 mL, 9.23 mmol). The reaction mixture wasstirred at room temperature under an inert atmosphere overnight. Thevolatiles were removed in vacuo with toluene to afford the freepiperazine linker phosphonate 182 (0.323 g, 100%) as a TFA salt: ¹H NMR(CDCl₃) δ 11.0 (bs, 1H), 4.2 (m, 4H), 3.45 (t, 4H), 3.35 (m, 4H), 3.2(d, 2H), 1.4 (t, 6H); ³¹P NMR (CDCl₃) δ 19.16 MS: 237 (M+1).

Example 183

A solution of the phenol intermediate 45 (0.044 mmol) in dichloromethane(0.441 mL) was treated with triethylamine (0.025 mL, 0.176 mmol) andcat. 4-dimethylaminopyridine. The reaction mixture was cooled to 0° C.then triphosgene (0.026 g, 0.088 mmol) in a 1M solution ofdichloromethane was added. The mixture stirred at room temperature underan inert atmosphere for 2 hours, then the free piperazine linkerphosphonate 182 (0.046 g, 0.132 mmol) in a 1M solution ofdichloromethane treated with triethylamine (0.025 mL, 0.176 mmol) wasadded, and the mixture was stirred overnight. The mixture waspartitioned between dichloromethane and water. The organic phase waswashed with saturated NH₄Cl and brine, dried (MgSO₄), and concentratedin vacuo. The residue was purified by silica gel chromatography(3/97—methanol/dichloromethane) to afford the product 183 (0.016 g,64%): ¹H NMR (CDCl₃) δ 9.05 (dd, 1H), 8.1 (dd, 1H), 8.0 (s, 1H), 7.75(d, 4H), 7.5 (dd, 1H), 7.4-7.m, 8H), 7.05 (t, 2H), 4.8 (s, 2H), 4.2 (s,2H), 4.15 (m, 4H), 3.75 (m, 2H), 3.6 (m, 2H), 2.85 (d, 2H), 2.8 (m, 2H),2.75 (m, 2H), 1.35 (t, 6H); ³¹P NMR (CDCl₃) δ 23.57; MS: 753 (M+1).

Example 184

A solution of the phosphonate 183 (0.016 g, 0.021 mmol) indichloromethane (0.5 mL) was treated with trifluoroacetic acid (0.1 mL)and triethylsilane (0.2 mL). The reaction mixture was stirred at roomtemperature under an inert atmosphere for 20 minutes. The volatiles wereremoved in vacuo with toluene. The solid was triturated indiethylether/hexane to afford the product 184 (0.0125 g, 100%) as a TFAsalt: ¹H NMR (CDCl₃) δ 9.0 (dd, 1H), 8.2 (dd, 1H), 7.6 (dd, 1H), 7.3 (m,2H), 7.05 (t, 2H), 4.75 (s, 2H), 4.35 (s, 2H), 4.2 (m, 4H), 3.95 (m,2H), 3.75 (m, 2H), 3.2 (d, 2H), 3.2 (m, 2H), 3.1 (m, 2H), 1.4 (t, 6H);³¹P NMR (CDCl₃) δ 19.93; MS: 587 (M+1), 585 (M−1).

Example 185

To a solution of (2-hydroxy-ethyl)-phosphonic acid dimethyl ester (0.250g, 1.62 mmol) in dichloromethane (4 mL) was added 2,6-lutidine (0.284mL, 2.44 mmol). The reaction mixture was cooled to 40° C. andtrifluoromethanesulfonic anhydride (0.355 mL, 2.11 mmol) was added. Themixture stirred in the cold bath under an inert atmosphere for 2 hoursat which point the reaction was completed as shown by ³¹P NMR (CDCl₃) δ25.7. The mixture was partitioned between dichloromethane and water bothcooled by an ice-water bath. The organic phase was washed with brine,dried (MgSO₄), and concentrated in vacuo to affordtrifluoromethanesulfonic acid dimethoxy-phosphoryl-2-ethyl ester 185 asan oil which was immediately carried forward with no furtherpurification or characterization.

Example 186

To a solution of 1-BOC-piperazine (0.252 g, 1.35 mmol) in acetonitrile(14.3 mL) was added CsCO₃ (1.32 g, 4.06 mmol) and then cooled to 0° C.Trifluoromethanesulfonic acid dimethoxy-phosphoryl-2-ethyl ester 185(0.464 g, 1.62 mmol) dissolved in acetonitrile (5 mL) was added in adropwise manner. The reaction mixture was stirred at room temperatureovernight upon which it was concentrated in vacuo. The reaction mixturewas taken into ethylacetate then washed with saturated NH₄Cl and brine,dried (MgSO₄), then concentrated in vacuo. The residue was purifiedusing silica gel chromatography (5/95-methanol/dichloromethane) toafford the BOC protected piperazine linker phosphonate 186 (0.162 g, 31%over 2 steps) as an oil: ¹H NMR (CDCl₃) δ 3.75 (d, 6H), 3.4 (m, 4H),2.65 (m, 2H), 2.4 (m, 4H), 1.95 (m, 2H), 1.45 (s, 9H); ³¹P NMR (CDCl₃) δ33.06; MS: 323 (M+1).

Example 187

A solution of the BOC protected piperazine linker phosphonate 186 (0.162g, 0.503 mmol) in dichloromethane (3.35 mL) was treated withtrifluoroacetic acid (0.388 mL, 5.03 mmol). The reaction mixture wasstirred at room temperature under an inert atmosphere overnight. Thevolatiles were removed in vacuo with toluene to afford the freepiperazine linker phosphonate 187 (0.169 g, 100%) as a TFA salt: ¹H NMR(CD₃OD) δ 3.8 (d, 6H), 3.45 (m, 4H), 3.2 (m, 4H), 3.15 (m, 2H), 2.3 (m,2H); ³¹P NMR (CDCl₃) δ 30.92; MS: 223 (M+1).

Example 188

A solution of the phenol intermediate 45 (0.046 mmol) in dichloromethane(0.458 mL) was treated with triethylamine (0.026 mL, 0.183 mmol) and acatalytic amount of 4-dimethylaminopyridine. The reaction mixture wascooled to 0° C. then triphosgene (0.027 g, 0.092 mmol) in a 1M solutionof dichloromethane was added. The mixture was stirred at roomtemperature under an inert atmosphere for 2 hours, then the freepiperazine linker phosphonate 187 (0.046 g, 0.137 mmol) in a 1M solutionof dichloromethane treated with triethylamine (0.026 mL, 0.183 mmol) wasadded dropwise. The mixture was stirred overnight and then partitionedbetween dichloromethane and water. The organic phase was washed withsaturated NH₄Cl and brine, dried (MgSO₄), and concentrated in vacuo. Theresidue was purified by silica gel chromatography(8/92-methanol/ethylacetate) to afford the product 188 (0.019 g, 56%):¹H NMR (CDCl₃) δ 9.05 (dd, 1H), 8.1 (dd, 1H), 8.05 (s, 1H), 7.75 (m,4H), 7.5 (dd, 1H), 7.4-7.1 (m, 8H), 7.1 (t, 2H), 4.8 (s, 2H), 4.2 (s,2H), 3.8 (d, 6H), 3.6 (m, 4H), 2.75 (m, 2H), 2.55 (m, 4H), 2.1 (m, 2H);³¹P NMR (CDCl₃) δ 32.65; MS: 739 (M+1).

Example 189

A solution of the phosphonate 188 (0.019 g, 0.026 mmol) indichloromethane (0.5 mL) was treated with trifluoroacetic acid (0.1 mL)and triethylsilane (0.2 mL). The reaction mixture was stirred at roomtemperature under an inert atmosphere for 20 minutes. The volatiles wereremoved in vacuo with toluene. The solid was triturated indiethylether/hexane to afford the product 189 (0.013 g, 74%) as a TFAsalt: ¹H NMR (CDCl₃) δ 8.9 (dd, 1H), 8.15 (dd, 1H), 7.55 (dd, 1H), 7.35(m, 2H), 7.05 (t, 2H), 4.75 (s, 2H), 4.35 (s, 2H), 4.2 (m, 2H), 3.95 (m,2H), 3.8 (d, 6H), 3.4 (m, 4H), 3.35 (m, 2H), 2.4 (m, 2H); ³¹P NMR(CDCl₃) δ 27.31; MS: 573 (M+1).

Example 190

A solution of the phosphonate 189 (0.006 g, 0.009 mmol) indichloromethane (0.088 mL) was treated with trimethylsilane bromide(0.007 mL, 0.053 mmol). The reaction mixture was stirred at roomtemperature overnight under an inert atmosphere. The volatiles wereremoved in vacuo with methanol. The solid was washed withdichloromethane to afford the diacid 190 (0.006 g, 100%): ¹H NMR (CD₃OD)δ 9.3 (dd, 1H), 9.2 (dd, 1H), 8.2 (dd, 1H), 7.4 (m, 2H), 7.1 (t, 2H),4.8 (s, 2H), 4.6 (s, 2H), 3.6-3.2 (m, 10H), 2.35 (m, 2H); ³¹P NMR(CD₃OD) δ 21.43; MS: 545 (M+1), 543 (M−1).

Example 191

To a solution of 2-[(2-oxo-ethyl)-phenoxy-phosphinoyloxy]-propionic acidethyl ester, aldehyde 166, as a 1:1 mixture of DMSO (0.050 g, 0.167mmol) and 1-BOC-piperazine (0.034 g, 0.183 mmol) dissolved in ethanol(1.67 mL) was added acetic acid (0.038 mL, 0.667 mmol). The reactionmixture was stirred at room temperature for 2.5 hours then sodiumcyanoborohydride (0.021 g, 0.333 mmol) was added. The reaction mixturestirred at room temperature overnight. Saturated NaHCO₃ was added to thereaction mixture and was stirred for five more minutes. The mixture wasconcentrated in vacuo to remove most of the ethanol. Brine was added andthen the crude product was extracted into ethylacetate. The organicphase was dried (MgSO₄) and concentrated. The residue was purified bysilica gel chromatography (5/95-methanol/dichloromethane) to afford theproduct 191 (0.050 g, 64%), an oil as a mixture of diastereomers: ¹H NMR(CDCl₃) δ 7.4-7.1 (m, 5H), 5.0 (m, 1H), 4.2 (m, 2H), 3.4 (m, 4H), 2.8(m, 2H), 2.4 (m, 4H), 2.2 (m, 2H), 1.6 & 1.35 (d, 3H), 1.4 (s, 9H), 1.2(t, 3H); ³¹P NMR (CDCl₃) δ 28.83, 27.18; MS: 471 (M+1).

Alternatively, a solution of2-[(2-oxo-ethyl)-phenoxy-phosphinoyloxy]-propionic acid ethyl ester 166,as a 1:1 mixture with DMSO (0.500 g, 1.67 mmol), andpiperazine-1-carboxylic acid tert-butyl ester (1-BOC-piperazine, 0.340g, 1.83 mmol) dissolved in ethanol (1.67 mL) was added 4 Å molecularsieves (0.300 g) and acetic acid (0.400 mL, 6.8 mmol). The reactionmixture was stirred at room temperature for 1.5 hours then sodiumcyanoborohydride (0.212 g, 3.33 mmol) was added. The reaction mixturestirred at room temperature for 3 hours and was concentrated in vacuothen redissolved in chloroform. The mixture was washed with saturatedNaHCO₃ and brine, dried (NaSO₄), filtered and concentrated. The residuewas treated with diethyl ether. Solid precipitate was filtered off, andthe filtrate was concentrated to afford4-{2-[(1-Ethoxycarbonyl-ethoxy)-phenoxy-phosphoryl]-ethyl}-piperazine-1-carboxylicacid tert-butyl ester 191 (0.600 g, 77%) as an oil (mixture of twodiastereomers).

Example 192

A solution of4-{2-[(1-ethoxycarbonyl-ethoxy)-phenoxy-phosphoryl]-ethyl}-piperazine-1-carboxylicacid tert-butyl ester 191 (0.050 g, 0.106 mmol) in dichloromethane(0.709 mL) was treated with trifluoroacetic acid (0.082 mL, 1.06 mol).The reaction mixture was stirred at room temperature under an inertatmosphere for 4 hours. The volatiles were removed in vacuo with tolueneto afford the free piperazine linker phosphonate 192 (0.051 g, 100%) asa TFA salt (mixture of two diastereomers): ¹H NMR (CDCl₃) δ 10.8 (bs,1H), 7.5-7.1 (m, 5H), 5.0 (m, 1H), 4.2 (m, 4H), 3.7 (m, 8H), 2.65 (m,2H), 1.6 & 1.4 (d, 3H), 1.25 (t, 3H); ³¹P NMR (CDCl₃) δ 25.58, 20.86;MS: 371 (M+1).

Alternatively a solution of4-{2-[(1-ethoxycarbonyl-ethoxy)-phenoxy-phosphoryl]-ethyl}-piperazine-1-carboxylicacid tert-butyl ester 191 (0.100 g, 0.212 mmol) in methylene chloride (2mL) was treated with trifluoroacetic acid (0.340 mL, 4.41 mmol). Thereaction mixture was stirred at room temperature under an inertatmosphere for 6 hours. The volatiles were removed in vacuo with ethylacetate to afford the trifluoroacetate salt of2-[phenoxy-(2-piperazin-1-yl-ethyl)-phosphinoyloxy]-propionic acid ethylester 192 (0.103 g, 100%) (mixture of two diastereomers).

Example 193

A solution of the phenol intermediate 45 (0.039 mmol) in dichloromethane(0.386 mL) was treated with triethylamine (0.022 mL, 0.155 mmol) andcat. 4-dimethylaminopyridine. The reaction mixture was cooled to 0° C.then triphosgene (0.023 g, 0.077 mmol) in a 1M solution ofdichloromethane was added. The mixture stirred at room temperature underan inert atmosphere for 2 hours, then the free piperazine linkerphosphonate 192 (0.056 g, 0.115 mmol) in a 1M solution ofdichloromethane treated with triethylamine (0.022 mL, 0.155 mmol) wasadded, and the mixture was stirred overnight. The mixture waspartitioned between dichloromethane and water. The organic phase waswashed with saturated NH₄Cl and brine, dried (MgSO₄), and concentratedin vacuo. The residue was purified by silica gel chromatography(5/95-methanol/dichloromethane) to afford the product 193 (0.013 g, 50%)as a mixture of diastereomers: ¹H NMR (CDCl₃) δ 9.05 (dd, 1H), 8.1 (dd,1H), 8.05 (s, 1H), 7.75 (d, 4H), 7.5 (dd, 1H), 7.4-7.1 (m, 11H), 7.05(t, 2H), 5.1 (m, 1H), 4.8 (s, 2H), 4.2 (s, 2H), 4.15 (m, 2H), 3.8-3.4(m, 4H), 3.0-2.2 (m, 8H), 1.6 & 1.4 (d, 3H), 1.2 (t, 3H); ³¹P NMR(CDCl₃) δ 28.30, 26.59; MS: 887 (M+1).

Example 194

A solution of the phosphonate 193 (0.013 g, 0.015 mmol) indichloromethane (0.5 mL) was treated with trifluoroacetic acid (0.1 mL)and triethylsilane (0.2 mL). The reaction mixture was stirred at roomtemperature under an inert atmosphere for 20 minutes. The volatiles wereremoved in vacuo with toluene. The solid was triturated indiethylether/hexane to afford the product 194 (0.010 g, 80%) as a TFAsalt: ¹H NMR (CDCl₃) δ 8.95 (dd, 1H), 8.15 (dd, 1H), 7.55 (dd, 1H), 7.35(m, 2H), 7.3-7.1 (m, 5H), 7.05 (t, 2H), 5.0 (m, 1H), 4.75 (s, 2H), 4.35(s, 2H), 4.2 (m, 21H), 3.8-3.6 (m, 4H), 3.4-3.0 (m, 6H), 2.5-2.7 (m,2H), 1.6 & 1.4 (d, 3H), 1.25 (t, 3H); ³¹P NMR (CDCl₃) δ 22.29, 21.67;MS: 721 (M+1).

Example 195

To a solution of 2-aminoethylphosphonic acid (1.26 g, 10.1 mmol) in 2NNaOH (10.1 mL, 20.2 mmol) was added benzyl chloroformate (1.7 mL, 12.1mmol). After the reaction mixture was stirred for 2 d at roomtemperature, the mixture was partitioned between Et₂O and water. Theaqueous phase was acidified with 6N HCl until pH=2. The resultingcolorless solid was dissolved in MeOH (75 mL) and treated with Dowex50WX8-200 (7 g). After the mixture was stirred for 30 minutes, it wasfiltered and evaporated under reduced pressure to givecarbobenzoxyaminoethyl phosphonic acid (2.37 g, 91%) as a colorlesssolid.

To a solution of carbobenzoxyaminoethyl phosphonic acid (2.35 g, 9.1mmol) in pyridine (40 mL) was added phenol (8.53 g, 90.6 mmol) and1,3-dicyclohexylcarbodiimide (7.47 g, 36.2 mmol). After the reactionmixture was warmed to 70° C. and stirred for 5 h, the mixture wasdiluted with CH₃CN and filtered. The filtrate was concentrated underreduced pressure and diluted with EtOAc. The organic phase was washedwith sat. NH₄Cl, sat. NaHCO₃, and brine, then dried over Na₂SO₄,filtered, and evaporated under reduced pressure. The crude product waschromatographed on silica gel twice (eluting 40-60% EtOAc/hexane) togive diphenyl 2-aminoethyl phosphonic acid (2.13 g, 57%) as a colorlesssolid.

To a solution of diphenyl 2-aminoethyl phosphonic acid (262 mg, 0.637mmol) in iPrOH (5 mL) was added TFA (0.05 mL, 0.637 mmol) and 10% Pd/C(26 mg). After the reaction mixture was stirred under H₂ atmosphere(balloon) for 1 h, the mixture was filtered through Celite. The filtratewas evaporated under reduced pressure to give diphenylcarbobenzoxyaminoethyl phosphonate 195 (249 mg, 100%) as a colorlessoil.

Example 196

To a solution of benzyloxymethyl phosphonic acid (520 mg, 2.57 mmol) inCH₃CN (5 mL) was added thionyl chloride (0.75 mL, 10.3 mmol) and heatedto 70° C. in an oil bath. After the reaction mixture was stirred for 2 hat 70° C., the mixture was concentrated and azeotroped with toluene. Toa solution of the crude chloridate in toluene (5 mL) was added tetrazole(18 mg, 0.26 mmol) at 0° C. To this mixture was added phenol (121 mg,1.28 mmol) and triethylamine (0.18 mL, 1.28 mmol) in toluene (3 mL) at0° C. After the reaction mixture was warmed to room temperature andstirred for 2 h, ethyl lactate (0.29 mL, 2.57 mmol) and triethylamine(0.36 mL, 2.57 mmol) in toluene (2.5 mL) were added. The reactionmixture was stirred for 16 hours at room temperature, at which time themixture was partitioned between EtOAc and sat. NH₄Cl. The organic phasewas washed with sat. NH₄Cl, 1M NaHCO₃, and brine, then dried overNa₂SO₄, filtered, and evaporated under reduced pressure. The crudeproduct was chromatographed on silica gel (eluting 20-40% EtOAc/hexane)to give two diastereomers (isomer A and isomer B) of2-(benzyloxymethyl-phenoxy-phosphinoyloxy)-propionic acid ethyl ester196 (66 mg, 109 mg, 18% total) as colorless oils.

Example 197a

To a solution of benzyl phosphonate 196 isomer A (66 mg, 0.174 mmol) inEtOH (2 mL) was added 10% Pd/C (13 mg). After the reaction mixture wasstirred under H₂ atmosphere (balloon) for 6 h, the mixture was filteredthrough Celite. The filtrate was evaporated under reduced pressure togive alcohol 197a isomer A (49 mg, 98%) as a colorless oil.

Example 197b

To a solution of benzyl phosphonate 196 isomer B (110 mg, 0.291 mmol) inEtOH (3 mL) was added 10% Pd/C (22 mg). After the reaction mixture wasstirred under H₂ atmosphere (balloon) for 6 h, it was filtered throughCelite. The filtrate was evaporated under reduced pressure to givealcohol 197b isomer B (80 mg, 95%) as a colorless oil.

Example 198a

To a solution of alcohol 197a isomer A (48 mg, 0.167 mmol) in CH₂Cl₂ (2mL) was added 2,6-lutidine (0.03 mL, 0.250 mmol) andtrifluoromethanesulfonic anhydride (0.04 mL, 0.217 mmol) at −40° C. (dryice-CH₃CN bath). After the reaction mixture was stirred for 15 min at−40° C., the mixture was warmed to 0° C. and partitioned between Et₂Oand 1M H₃PO₄. The organic phase was washed with 1M H₃PO₄ (3 times),dried over Na₂SO₄, filtered, and evaporated under reduced pressure togive triflate 198a isomer A (70 mg, 100%) as a pale yellow oil.

Example 198b

To a solution of alcohol 197b isomer B (80 mg, 0.278 mmol) in CH₂Cl₂ (3mL) was added 2,6-lutidine (0.05 mL, 0.417 mmol) andtrifluoromethanesulfonic anhydride (0.06 mL, 0.361 mmol) at −40° C. (dryice-CH₃CN bath). After the reaction mixture was stirred for 15 min at−40° C., the mixture was warmed to 0° C. and partitioned between Et2Oand 1M H₃PO₄. The organic phase was washed with 1M H₃PO₄ (3 times),dried over Na₂SO₄, filtered, and evaporated under reduced pressure togive triflate 198b isomer B (115 mg, 98%) as a pale yellow oil.

Example 199

To a stirred solution of phenyl 2-carbobenzoxyaminoethyl phosphonate (1g, 3 mmol) in 30 mL of acetonitrile at room temperature under N₂ wasadded thionyl chloride (0.67 mL, 9 mmol). The resulted mixture wasstirred at 60-70° C. for 0.5 h. After cooled to room temperature, thesolvent was removed under reduced pressure, and the residue was added 30mL of DCM, followed by DIEA (1.7 mL, 10 mmol), L-alanine butyric acidethyl ester hydrochloride (1.7 g, 10 mmol) and TEA (1.7 mL, 12 mmol).After 4 h at room temperature, the solvent was removed under reducedpressure, and the residue was diluted with DCM and washed with brine andwater, dried over Na₂SO₄, filtered and concentrated. The residue waspurified by chromatography on silica gel (Hexane/EtOAc 1:1) to give 199(670 mg, 50%) as a yellow oil. ¹NMR (CDCl₃) δ 7.33-7.11 (m, 10H), 5.70(m, 1H), 5.10 (s, 2H), 4.13-3.53 (m, 5H), 2.20-2.10 (m, 2H), 1.76-1.55(m, 2H), 1.25-1.19 (m, 3H), 0.85-0.71 (m, 3H); ³¹P NMR (CDCl₃) δ 30.2and 29.9; MS (ESI) 471 (M+Na).

Example 200

A solution of compound 199 (450 mg) was dissolved in 9 mL of EtOH, then0.15 mL of acetic acid and 10% Pd/C (90 mg) was added. The resultedmixture was stirred under H2 atmosphere (balloon) for 4 h. Afterfiltration through Celite, the filtered was evaporated under reducedpressure to afford the compound 200 (300 mg, 95%) as a colorless oil. ¹HNMR (CDCl₃) δ 7.29-7.12 (m, 5H), 4.13-3.53 (m, 5H), 2.20-2.10 (m, 2H),1.70-1.55 (m, 2H), 1.24-1.19 (m, 3H), 0.84-0.73(m, 3H); ³¹P NMR (CDCl₃)δ 29.1 and 28.5; MS (ESI) 315 (M+1).

Example 201

A THF solution (30 mL) of NaH (3.4 g of 60% oil dispersion, 85 mmol) wascooled to −10° C., followed by the addition ofdiethyl(cyanomethyl)phosphonate (5 g, 28.2 mmol) and iodomethane (17 g,112 mmol). The resulting solution was stirred at −10° C. for 2 hr, then0° C. for 1 hr, was worked up, and purified to givediethyl(cyano(dimethyl)methyl)phosphonate (5 g, 86%).

Diethyl(cyano(dimethyl)methyl)phosphonate was reduced to the aminederivative by the described procedure (J. Med. Chem. 1999, 42,5010-5019) whereby a solution of ethanol (150 mL) and 1N HCl aqueoussolution (22 mL) of diethyl(cyano(dimethyl)methyl)phosphonate (2.2 g,10.7 mmol) was hydrogenated at 1 atmosphere in the presence of PtO₂(1.25 g) at room temperature overnight. The catalyst was filteredthrough a Celite pad. The filtrate was concentrated to dryness, to givecrude diethyl 2-amino-1,1-dimethyl-ethyl phosphonate (2.5 g, as HClsalt).

Crude diethyl 2-amino-1,1-dimethyl-ethyl phosphonate (2.5 g) in 30 mLCH₃CN was cooled to 0° C., and treated with TMSBr (8 g, 52 mmol) for 5hr. The reaction mixture was stirred with methanol for 1.5 hr at roomtemperature, concentrated, recharged with methanol, concentrated todryness to give crude 2-Amino-1,1-dimethyl-ethyl phosphonic acid whichwas used for next reaction without further purification.

2-Amino-1,1-dimethyl-ethyl phosphonic acid was protected with CBZ,followed by the reaction with thionyl chloride at 70° C. The CBZprotected dichloridate was reacted with phenol in the presence of DIPEA.Removal of one phenol, follow by coupling with ethyl L-lactate gaveN-CBZ-2-amino-1,1-dimethyl-ethyl phosphonate derivative. Hydrogenationof N-CBZ derivative at 1 atmosphere in the presence of 10% Pd/C and 1eq. of TFA gave lactate phenyl (2-amino-1,1-dimethyl-ethyl)phosphonate201 as the TFA salt.

Example 202

Powdered magnesium tert-butoxide (2.05 g, 12.02 mmol) was added to asolution of dibenzyl trifluoromethane sulfonic hydroxymethyl phosphonate(4.10 g, 9.66 mmol) and anhydrous ethylene glycol (5.39 mL, 96.6 mmol)in anhydrous DMF (30 mL) at 0° C. The reaction mixture was stirred at 0°C. for 1.5 h, then concentrated. The residue was partitioned betweenEtOAc and H₂O and washed with 1 N HCl, saturated NaHCO₃ solution, andbrine. Organic layer dried (MgSO₄), concentrated and purified (silicagel, 4% MeOH/CH₂Cl₂) to give (2-hydroxy-ethoxymethyl)-phosphonic aciddibenzyl ester 202 as a colorless oil (1.55 g, 48%). ¹H NMR (300 MHz,CDCl₃): δ 7.37 (s, 10 H, Ar), 5.40-5.05 (m, 4 H, CH₂Ph), 3.84 (d, J=8.1Hz, 2 H, PCH₂O), 3.70-3.60 (m, 4 H, OCH₂CH₂O, OCH₂CH₂O); ³¹P NMR (121MHz, CDCl₃): δ 22.7.

Example 203

A solution of 24 (Example 24) (38 mg, 0.086 mmol) in CH₂Cl₂ (0.86 mL)was stirred with EDC (33 mg, 0.172 mmol), TEA (12 μL, 0.086 mmol), and1-Boc-piperazine (19 mg, 0.103 mmol) at ambient temperature for 15 hwhen LCMS analysis demonstrated completion of the reaction. The reactionmixture was worked up by dilution of the mixture with CH₂Cl₂ and washingthe organic layer with H₂O. The organic layer was dried in vacuo and theresidue,4-{3-[7-(4-fluoro-benzyl)-9-hydroxy-5-methoxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-6-ylsulfanyl]-propionyl}-piperazine-1-carboxylicacid tert-butyl ester 203 was carried forward for deprotection.

Example 204

A solution of 203 (52 mg, 0.085 mmol) in 0.8 mL of trifluoroacetic acidand 0.8 mL of CH₂Cl₂ was stirred at room temperature for 1 h when thestarting material was completely consumed as detected by LCMS. Thesolution was dried in vacuo and redissolved in 1:1 mixture of MeOH—H₂O.The product 204 was purified by RP-HPLC using a 5-95% A. Buffer Acontained CH₃CN-1% TFA and buffer B was H₂O-1% TFA. ¹H NMR (300 MHz,CD₃OD) δ 2.19-2.40 (m, 4H), 3.06-3.20 (m, 4H), 3.43-3.56 (m, 2H),3.63-3.74 (m, 2H), 4.08 (s, 3H), 4.62 (d, 1H, J=15 Hz), 5.16 (d, 1H,J=15 Hz), 5.76 (s, 1H), 7.10 (t, 2H, J=9 Hz), 7.46 (t, 2H, J=8 Hz), 7.74(dd, 1H, J=4, 8 Hz), 8.69 (d, 1H, J=8 Hz), 8.96 (d, 1H, J=4 Hz); ¹⁹F NMR(282.6 MHz, CD₃OD) δ −77.7, 60.0; EI MS (m/z) 511.0 [M+H⁺.

Example 205

Grignard product 16 (Example 16) was worked up by addition of ethylacetate and stirring of the organic layer with aqueous 1N HCl for 30minutes. The layers were separated and the organic layer was washed withthe 1N HCl solution 2 more times. The organic layer was checked withLCMS to assure complete elimination of the alcohol resulted from theGrignard reaction to the eliminated product 205. The organic layer wasdried in vacuo and the residue was purified by column chromatographyusing CH₂Cl₂ to give 205. ¹H NMR (300 MHz, CDCl₃) δ 1.15 (d, 18H, J=8Hz), 1.56 (septet, 3H, J=8 Hz), 3.95 (s, 3H), 4.82 (s, 1H), 4.99 (s,2H), 5.53 (s, 1H), 7.01 (t, 2H, J=8 Hz), 7.28 (dd, 2H, J=5, 9 Hz), 7.54(dd, 1H, J=4, 8 Hz), 8.46 (d, 1H, J=8 Hz), 8.87 (d, 1H, J=3 Hz); ¹⁹F NMR(282.6 MHz, CDCl₃) δ 61.06; EI MS (m/z) 507.4 [M+H]⁺.

Example 206

A solution of diethylzinc (0.134 mmol, 134 μL of a 1M mixture) and 134μL of CH₂Cl₂ was added to TFA (0.134 mmol, 10.4 μL) under a N₂atmosphere at 0° C. The mixture was stirred at cooled temperature for 15minutes, then a solution of CH₂I₂ (0.134 mmol, 11 μL) in 100 μL ofCH₂Cl₂ was added. After 10 minutes, a solution of 205 in 100 μL ofCH₂Cl₂ was added and the ice bath removed. The reaction mixture wasstirred at ambient temperature for 1 hour when LCMS analysisdemonstrated complete consumption of the starting materials. The product206 was purified by RP-HPLC using a 20-80% A. Buffer A containedCH₃CN-1% TFA and buffer B was H₂O-1% TFA. ¹H NMR (300 MHz, CD₃OD) δ 1.58(t, 2H, J=5 Hz), 1.79 (t, 2H, J=5 Hz), 3.95 (s, 3H), 4.61 (s, 2H), 7.07(t, 2H, J=9 Hz), 7.32 (dd, 2H, J=5, 8 Hz), 7.84 (dd, 1H, J=4, 8 Hz),8.77 (d, 1H, J=8 Hz), 8.98 (d, 1H, J=4 Hz); ¹⁹F NMR (282.6 MHz, CD₃OD) δ−78.0, 59.3; EI MS (m/z) 365.3 [M+H]⁺, 387.3 [M+Na]⁺.

Example 207

A solution of 12 (Example 12, 65 mg, 0.131 mmol) in 1.3 mL of CH₂Cl₂ wasstirred with dimethyl sulfamoyl chloride (38 mg, 0.262 mmol), TEA (73μL, 0.63 mmol), and DMAP (2 mg, 0.013 mmol) for 2 hours at roomtemperature when LCMS analysis demonstrated complete consumption of thestarting materials. The reaction was worked up by dilution with CH₂Cl₂and washing the organic layer with H₂O. The solvent was removed underreduced pressure and the product was purified by column chromatographyto yield 59 mg of 207 (75%) as a white solid. ¹H NMR (300 MHz, CDCl₃) δ1.12 (d, 18H, J=8 Hz), 1.53 (septet 3H, J=8 Hz), 3.23 (s, 6H), 4.84 (s,2H), 7.00 (t, 2H, J=8 Hz), 7.45 (dd, 2H, J=6, 9 Hz), 7.65 (dd, 1H, J=4,8 Hz), 8.77 (dd, 1H, J=2, 8 Hz), 8.94 (dd, 1H, J=2, 4 Hz); ¹⁹F NMR(282.6 MHz, CDCl₃) δ 62.0; EI MS (m/z) 624.2 [M+Na]⁺.

Example 208

A solution of 207 (30 mg, 0.050 mmol) in 0.25 mL of THF was stirred with33 μL (0.10 mmol) of methylmagnesium bromide for 1 hour at roomtemperature. The solution was diluted with CH₂Cl₂ and stirred withaqueous 1N HCl for 30 minutes. Removal of the solvent in vacuo yielded26 mg (87%) of the product 208 as a green oil. ¹H NMR (300 MHz, CDCl₃) δ1.14 (d, 18H, J=8 Hz), 1.56 (septet, 3H, J=8 Hz), 2.97 (s, 6H), 4.94 (s,1H), 5.00 (s, 2H), 5.59 (s, 1H), 7.00 (t, 2H, J=8 Hz), 7.21-7.32 (m,2H), 7.55-7.62 (m, 1H), 8.50 (d, 1H, J=8 Hz), 8.88 (br s, 1H); ¹⁹F NMR(282.6 MHz, CDCl₃) δ 61.3; EI MS (m/z) 600.2 [M+H]⁺, 622.2 [M+Na]⁺.

Example 209

A solution of 208 (13 mg, 0.022 mmol) and TFA (0.11 mL) and CH₂Cl₂ (0.11mL) was allowed to stir at room temperature overnight. The solvent wasremoved in vacuo and the residue was purified by RP-HPLC using a 20-80%A to give product 209. Buffer A contained CH₃CN-1% TFA and buffer B wasH₂O-1% TFA. ¹H NMR (300 MHz, CDCl₃) δ 3.06 (s, 3H), 3.07 (s, 3H), 5.00(s, 2H), 5.12 (s, 1H), 5.71 (s, 1H), 6.96-7.07 (m, 2H), 7.22-7.33 (m,2H), 7.71 (dd, 1H, J=4, 9 Hz), 8.67 (d, 1H, J=8 Hz),9.05 (br s, 1H); ¹⁹FNMR (282.6 MHz, CDCl₃) −76.2, 62.1; EI MS (m/z) 444.2 [M+H]⁺, 466.1[M+Na]⁺.

Example 210

Under a N₂ atmosphere, a solution of 208 (14 mg, 0.023 mmol) in CH₂Cl₂(0.23 mL) was stirred with triethylsilane (15 μL, 0.093 mmol) and borontrifluoride diethyletherate (BF₃OEt₂, 20 μL, 0.164 mmol) at ambienttemperature overnight. The reaction mixture was worked up by removingthe solvent under reduced pressure and precipitation from EtOAc-Hex toprovide 7.5 mg of the product 210 as a yellow solid. ¹H NMR (300 MHz,CDCl₃) δ 1.56 (d, 3H, J=7 Hz), 3.16 (s, 6H), 4.42 (d, 1H, J=15 Hz), 5.02(q, 1H, J=6 Hz), 5.09 (d, 1H, J=15 Hz), 7.06 (t, 2H, J=8 Hz), 7.33(dd,2H, J=5, 9 Hz), 7.72-7.79 (m, 1H), 8.62 (d, 1H, J=9 Hz), 9.15 (br s,1H); ¹⁹F NMR (282.6 MHz, CDCl₃) δ −76.2, 62.5; EI MS (m/z) 446.2 [M+H]⁺,468.2 [M+Na]⁺.

Example 211

Under a N₂ atmosphere, to a solution of diethylzine (0.074 mmol, 74 μLof a 1M mixture) and 74 μL of CH₂Cl₂ was added TFA (0.074 mmol, 5.7 μL)at 0° C. This mixture was stirred at cooled temperature for 15 minuteswhen a solution of CH₂I₂ (0.074 mmol, 6 μL) in 50 μL of CH₂Cl₂ wasadded. After 10 minutes, a solution of 208 in 50 μL of CH₂Cl₂ was addedand the ice bath removed. The reaction mixture was stirred at ambienttemperature for 1 hour when LCMS analysis demonstrated completeconsumption of the starting materials. The product 211 was purified byRP-HPLC using a 20-80% A. Buffer A contained CH₃CN-1% TFA and buffer Bwas H₂O-1% TFA. ¹H NMR (300 MHz, CD₃OD) δ 1.46 (br t, 2H), 2.10 (br t,2H), 3.14 (s, 6H), 4.55 (s, 2H), 7.02 (t, 2H, J=9 Hz), 7.21-7.31 (m,2H), 7.60-7.68 (m, 1H), 8.58-8.65 (m, 1H), 9.05-9.08 (m:, 1H); EI MS(m/z) 458.2 [M+H]⁺, 480.1 [M+Na]⁺.

Example 212

To trifluoro-methanesulfonic acid9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-5-ylester 46 (1.48 g, 2.39 mmol) and 1,3-bis(diphenylphosphino)propane(DPPP) (295 mg, 0.7 mmol) in DMF (20 mL) and water (1 mL) in atwo-necked round bottom flask were added Pd(OAc)₂ (107 mg, 0.48 mmol).The solution was degassed under high vacuum and flushed with carbonmonoxide from a balloon. The flushing was repeated five times. TEA(0.733 mL, 3.26 mmol) was introduced. The mixture was heated under COatmosphere for 2.5 hours and cooled down to the room temperature. MeI(0.74 mL, 12 mmol) and Cs₂CO₃ were added and stirring was continuedunder a nitrogen atmosphere for 45 minutes. The mixture was diluted withEtOAc (300 mL), washed with water, 1N aqueous HCl and brine, dried overMgSO₄ and concentrated. The crude product was purified by chromatographyon a silica gel column eluting with 15% to 35% of EtOAc in hexane toafford9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-5-carboxylicacid methyl ester 212, (0.9 g, 1.69 mmol, 70%) as a yellow solid. ¹H NMR(CDCl₃): δ9.25 (d, 1H), 9.05 (m, 1H), 7.80 (d, 4H), 7.56 (dd, 1H),7.0-7.4 (m, 11H), 4.85 (s, 2H), 4.55 (s, 2H), 3.95 (s, 3H); MS: 555(M+Na).

Example 213

A solution of9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-5-carboxylicacid methyl ester 212 (54 mg, 0.10 mmol) in 1.0 mL of a 1:1:1 mixture ofTHF: MeOH: H₂O was stirred with LiOH (9.7 mg, 0.41 mmol) overnight whenthe starting materials were completely consumed as judged by TLC(DPM=benzhydryl, Ph₂CH—). The reaction mixture was dried under reducedpressure and the residue was dissolved in EtOAc. The organic layer wasstirred with saturated aqueous NH₄Cl for 30 minutes. The aqueous layerwas checked by TLC to assure complete transfer of the products to theorganic layer. The organic layer was dried in vacuo to yield 45.5 mg(87%) of9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolio[3,4-g]quinoline-5-carboxylicacid 213 as a white solid. The product was carried on withoutpurification. MS (m/z) 519.2 [M+H]⁺, 541.2 [M+Na]⁺.

Alternatively, methyl ester 212 (0.071 g, 0.1334 mmol) was dissolved in2.4 mL of tetrahydrofuran and 0.6 mL of DI H₂O. To this was added LiOH(0.013 g, 0.5338 mmol) and mixture stirred at room temperature. After 15hours, starting material consumed. Diluted with dichloromethane, washedwith 1M HCl solution, dried (Na₂SO₄), concentrated to give 213 (0.068 g,0.1313 mmol, 98%.) ¹H NMR (CD₃SOCD₃) δ 9.25 (d, 1H), 9.12 (dd, 1H), 8.17(s, 1H), 7.75 (d, 5H), 7.37 (dd, 2H), 7.24 (m, 6H), 4.82 (s, 2H), 4.59(s, 2H.) MS: 517 (M−1.)

Example 214

A solution of the oxalate salt (HO₂CCO₂ ⁻) ofdiethyl(aminoethyl)phosphonate (12 mg, 0.042 mmol) in 0.21 mL of DMF wasmixed with DIEA (15 μL, 0.084 mmol) until the reaction became clear. Tothis solution was added 213 (11 mg, 0.021 mmol) andO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) (16 mg, 0.042 mmol). This mixture was stirredat room temperature for 2 hours when it was warmed to 60° C. with a heatgun for 1 minute. LCMS analysis demonstrated complete consumption of thestarting materials. The reaction mixture was directly loaded onto asilica gel column and the product was quickly eluted with a gradient ofEtOAc-10% MeOH/EtOAc to provide 12.7 mg (88%) of the product 214. ¹H NMR(300 MHz, CD₃OD) δ 1.29 (t, 6, J=7 Hz), 2.18 (dt, 2H, J'7, 18 Hz),3.53-3.65 (m, 2H), 4.08 (septet, 4H, J=7 Hz), 4.46 (s, 2H), 4.83 (s,2H), 7.06-7.25 (m, 8H), 7.40 (dd, 2H, J=5, 9 Hz), 7.61-7.68 (m, 6H),8.04 (s, 1H), 8.44 (d, 1H, J=7 Hz), 9.04-9.09 (m, 1H); ³¹P (121.4 MHz,CD₃OD) δ 29.5; MS (m/z) 682.1 [M+H]⁻, 704.2 [M+Na]⁺.

Example 215

A solution of 214 (12.7 mg, 0.019 mmol) in 0.19 mL of CH₂Cl₂ was stirredwith TFA (144 μL, 1.9 mmol) and TES (304 μL, 1.9 mmol) for 45 minutesunder a N₂ atmosphere. TLC and LCMS analysis indicated complete reactionat that time. The reaction was worked up by removing the solvent underreduced pressure. The residue was purified by crystallization fromEtOAc-Hex to yield 8.6 mg (71%) of(2-{[7-(4-fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-5-carbonyl]-amino}-ethyl)-phosphonicacid diethyl ester 215 as a yellow solid. ¹H NMR (500 MHz, CD₃OD) δ 1.33(t, 6H, J=7 Hz), 2.24 (dt, 2H, J=19, 7 Hz), 3.70 (septet, 2H, J=8 Hz),4.09-4.17 (m, 4H), 4.61 (s, 2H), 4.78 (s, 2H), 7.10 (t, 2H, J=9 Hz),7.41 (dd, 2H, J=6, 8 Hz), 7.76 (br d, 1H, J=5 Hz), 8.71 (d, 1H, J=9 Hz),8.95 (br s, 1H); ³¹P (121.4 MHz, CD₃OD) δ 29.5; MS (m/z) 516.3 [M+H]⁺,1030.9 [2M]⁺, 1053.0 [2M+Na]⁺.

Example 216

A solution of oxalate salt of diethyl(aminomethyl)phosphonate (8 mg,0.031 mmol) in 0.31 mL of DMF and DIEA (22 μL, 0.124 mmol) was added to213 (16 mg, 0.031 mmol) and HATU (24 mg, 0.062 mmol). The solution wasstirred at ambient temperature for 2 hours when another batch of theamine and the coupling reagent equivalent to the above amounts wereadded. The reaction was heated with a heat gun to 60° C. for 1 minuteand the reaction was analyzed by LCMS. The reaction mixture was loadedonto a flash column and({[9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-5-carbonyl]-amino}-methyl)-phosphonicacid diethyl ester 216 was eluted with EtOAc-10% MeOH to provide 20 mg(97%) of a clear oil. MS (m/z) 668.1 [M+H]⁺, 690.3 [M+Na]⁺.

Example 217

A solution of 216 (20 mg, 0.030 mmol) in 0.30 nL of CH₂Cl₂ was stirredwith TFA (231 μL, 3.00 mmol) and TES (479 μL, 3.00 mmol) for 30 minuteswhen the starting materials were completely consumed as judged by TLCand LCMS. The reaction was worked up by removal of the solvent in vacuoand crystallizing the product from EtOAc-Hex to provide 10 mg (66%) of({[7-(4-Fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-5-carbonyl]-amino}-methyl)-phosphonicacid diethyl ester 217 as a yellow solid. ¹H NMR (300 MHz, CD₃OD) δ 1.32(t, 6H, J=7 Hz), 3.96 (d, 2H, J=12 Hz), 4.16 (septet, 4H, J=7 Hz), 4.56(s, 2H), 4.79 (s, 2H), 7.10 (t, 2H, J=9 Hz), 7.39 (dd, 2H, J=9 Hz), 7.76(br s, 1H), 8.66 (d, 1H, J=8 Hz), 8.95 (br s, 1H); ³¹P (121.4 MHz,CD₃OD) δ 23.2; ¹⁹F NMR (282.6 MHz, CD₃OD) δ−76.2, 59.9; MS (m/z) 502.5[M+H]⁺, 1003.0 [2M]⁺, 1025.1 [2M+Na]⁺.

Example 218

S-lactate ester 218

Example 219

A solution of2-[(2-benzyloxycarbonylamino-ethyl)-phenoxy-phosphinoyloxy]-propionicacid ethyl ester 218 (240 mg, 0.551 mmol) with approximately 50% purityand a ratio of 2:1 of diastereomers was dissolved in 5.5 mL of ethanolwith acetic acid (63 μL, 1.10 mmol). To this solution was added 36 mg of10% Pd/C and the solution was degassed under a hydrogen atmosphere threetimes. The solution was vigorously stirred at room temperature for 3hours when TLC showed complete consumption of the starting materials.The mixture was filtered through a pad of Celite and dried to provide174 mg (87%) of 2-[(2-amino-ethyl)-phenoxy-phosphinoyloxy]-propionicacid ethyl ester; compound with acetic acid 219 as a clear oil.

Example 220

A solution of 13.5 mg of 213 in 0.13 mL of DMF was stirred with HATU (20mg, 0.052 mmol) at room temperature for 10 minutes. To this solution wasadded a premixed solution of 219 (28 mg, 0.078 mmol) of approximately50% purity in 0.130 mL of DMF and DIEA (13.4 mg, 0.104 mmol). Thereaction mixture was gently heated with a heat gun for 30 seconds andthen the reaction was allowed to proceed at room temperature for 2 hourswhen LCMS demonstrated complete consumption of the carboxylic acid. Thereaction mixture was loaded onto a silica gel column and purified withEtoAc-10% MeOH to provide 9.5 mg of3-[(2-{[9-Benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-5-carbonyl]-amino}-ethyl)-phenoxy-phosphinoyl]-2-methyl-propionicacid ethyl ester 220 which was carried on to the next step.

Example 221

A solution of 220 (9.5 mg, 11.8 μmol) was stirred with 0.12 mL of drydichloromethane with trifluoroacetic acid (93 μL, 1.18 mmol) andtriethylsilane (189 μL, 1.18 mmol) for 1 hour at room temperature whenTLC showed complete consumption of the starting materials. The reactionmixture was dried in vacuo and azeotroped from dichloromethane threetimes. The solid product was triturated with EtOAc-Hex to get 6 mg of2-[(2-{[7-(4-Fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-5-carbonyl]-amino}-ethyl)-phenoxy-phosphinoyloxy]-propionicacid ethyl ester 221 as a pale yellow solid. The NMR of the twodiastereomers in CDCl₃ is broad and indicates presence of rotamers. VTNMR in DMSO at 85° C. resulted in drastic sharpening of the peaks. ¹HNMR (300 MHz, DMSO-d6, 85° C.) δ 1.15-1.26 (m, 3H), 1.35 and 1.47 (d,3H, J=7 Hz), 2.23-2.45 (m, 2H), 3.58-3.57 (m, 2H), 4.08-4.19 (m, 2H),4.56 (s, 2H), 4.69 (s, 2H), 4.93-5.04 (n, 1IH), 7.14 (t, 2H, J=9 Hz),7.18-7.23 (m, 3H), 7.35-7.42 (m, 4H), 7.65 (dd, 1H, J=4, 8 Hz), 8.42 (brs, 1H), 8.55 (d, 1H, J=9 Hz), 8.92 (d, 1H, J=4H); ³¹P (121.4 MHz,DMSO-d6, 85° C.) δ 26.1, 28.3; MS (m/z) 636.5 [M+H]⁺.

Example 222

A solution of the trifluoroacetate salt of4-{2-[(1-ethoxycarbonyl-ethoxy)-phenoxy-phosphoryl]-ethyl}-piperazine-1-carboxylicacid7-(4-fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-5-ylester 194 (0.045 g, 0.054 mmol) in acetonitrile (ACN, 0.68 mL) and water(0.68 mL) was treated with an aqueous solution of NaOH (0.162 mL, 1M).The reaction mixture was stirred at room temperature for 3 hours. Themixture was cooled to 0° C., then acidified with a 2N aqueous solutionof HCl to pH=1. Acetonitrile was removed in vacuo then purified byreversed phase HPLC to afford the trifluoroacetate salt of4-{2-[(1-carboxy-ethoxy)-hydroxy-phosphoryl]-ethyl}-piperazine-1-carboxylicacid7-(4-fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-5-ylester; compound with trifluoro-acetic acid 222 (0.032 g, 80%): ¹H NMR(CD₃OD) δ 9.0 (d, 1H), 8.5 (d, 1H), 7.75 (dd, 1H), 7.4 (dd, 2H), 7.1 (t,2H), 4.8 (s, 2H), 4.45 (s, 2H), 4.3-3.7 (m, 4H), 3.7-3.35 (m, 6H), 2.2(m, 2H), 1.55 (d, 3H); ³¹P NMR (CDCl₃) δ 19.8; MS: 617 (M+1).

Example 223

A solution of the9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-5-carboxylicacid 213 (0.415 g, 0.80 mmol) and HATU (0.608 g, 1.60 mmol) inN,N-dimethylformamide (DMF) (2.5 mL) was stirred under an inertatmosphere at room temperature for 5 minutes. To the solution was addeda premixed solution of2-[phenoxy-(2-piperazin-1-yl-ethyl)-phosphinoyloxy]-(S)-propionic acidethyl ester: compound with trifluoroacetic acid 192 (0.580 g, 1.20mmol), N,N-Diisopropylethylamine (DIPEA) (0.700 mL, 4.0 mmol) in DMF(3.5 mL). The reaction mixture was stirred at room temperature for 5hours. The mixture was diluted with ethyl acetate, washed with saturatedNaHCO₃ (twice), water (twice) and brine (twice), dried (NaSO₄), andconcentrated. The residue was purified by silica gel chromatography(5/95-methanol/methylene chloride) to afford2-[(2-{4-[9-benzyhydryloxy-7-(4-fluoro-benzyl-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-5-carbonyl]-piperazin-1-yl}-ethyl)-phenoxy-phosphinoyloxy]-(S)-propionicacid ethyl ester 223 (0.625 g, 90%) as mixture of diastereomers: ¹H NMR(CDCl₃) δ 9.07 (dd, 1H), 8.15 (s, 1H), 8.05 (dd, 1H), 7.75 (d, 4H), 7.52(dd, 1H), 7.4-7.1 (m, 13H), 7.05 (t, 2H), 5.02 (m, 1H), 5.0-4.6 (dd,2H), 4.4-4.0 (dd, 2H), 4.17 (m, 2H), 4.0-3.5 (m, 3H), 3.0 (m, 2H),2.7-2.5 (m, 3H), 2.4-2.1 (m, 4H), 1.6 & 1.4 (d, 3H), 1.25 (t, 3H) ; ³¹PNMR (CDCl₃) δ 28.3, 26.5; MS: 871 (M+1).

Example 224

A solution of2-[(2-{4-[9-benzyhydryloxy-7-(4-fluoro-benzyl-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-5-carbonyl]-piperazin-1-yl}-ethyl)-phenoxy-phosphinoyloxy]-propionicacid ethyl ester 223 (0.420 g, 0.483 mmol) in methylene chloride (2 mL)was treated with trifluoroacetic acid (0.4 mL) and triethylsilane (0.8mL). The reaction mixture was stirred at room temperature under an inertatmosphere for 40 minutes. The volatiles were removed in vacuo withtoluene. The product was triturated in diethyl ether/hexane withsonicaton to afford the trifluoroacetate salt of2-{[2-4-2-[7-(4-fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-5-yl]-acetyl}-piperazin-1-yl)-ethyl]-phenoxy-phosphinoyloxy}-propionicacid ethyl ester 224 (0.370 g, 94%): ¹H NMR (CDCl₃) δ 9.0 (d, 1H), 8.15(dd, 1H), 7.67 (dd, 1H), 7.35-7.1 (m, 7H), 7.05 (t, 2H), 5.0 (m, 1H),5.0-4.6 (m, 2H), 4.6-4.25 (m, 2H), 4.25-3.95 (m, 5H), 3.7-2.8 (m, 8H),2.7-2.5 (m, 2H), 1.6 & 1.4 (d, 3H), 1.25 (t, 3H); ³¹P NMR (CDCl₃) δ23.0, 21.0; MS: 705 (M+1).

Example 225

Trimethylsilylethyl ether 44 (0.03 g, 0.0508 mmol) was dissolved in 2 mLdry tetrahydrofuran. To this was added triethylamine (0.028 mL, 0.2032mmol) and 1 M tetrabutylammonium fluoride solution in tetrahydrofuran(0.1016 mL, 0.1016 mmol.) Stirred at room temperature I0 minutes untilstarting material consumed. Diluted with dichloromethane, washed withwashed with 1M HCl solution, saturated brine, concentrated to givecrude. Dissolved in 1.5 mL dichloromethane, added catalyticdimethylaminopyridine, triethylamine (0.16 mL, 0.6 mmol) and cooled to0° C. To this was added triphosgene (0.03 g, 0.1016 mmol) and stirred 40minutes. BOC-aminopyrrolidine (0.038 g, 0.2032 mmol) was then added andstirred at room temperature for 10 minutes. The mixture was diluted withdichloromethane, washed with 1M HCl, brine, concentrated volatiles togive crude product. Chromatographed (10% to 30% acetone/toluene) to give225 (0.0108 g, 0.0153 mmol, 30%.) ¹H NMR (CDCl₃) δ 9.03 (dd, 1H), 8.11(d, 1H), 8.03 (s, 1H), 7.74 (d, 4H), 7.50 (dd, 1H), 7.27 (m, 8H), 7.07(dd, 2H), 4.80 (s, 2H), 4.65 (br s, 1H), 4.30 (hr s, 1H), 4.24 (s, 2H),3.95 (br s, 1H), 3.74 (m, 2H), 3.58 (m, 2H), 1.48 (s, 9H) MS: 703 M+1)

Example 226

Carbamate 225 (0.0108 g, 0.0153 mmol) was dissolved in 0.5 mL ofdichloromethane. To this was added 0.2 mL of triethylsilane and 0.1 mLof trifluoroacetic acid. Stirred at room temperature and after tenminutes complete by TLC. Concentrated off volatiles, azeotroped withtoluene to give crude. Then dissolved in 0.3 mL dichloromethane, 0.3 mltrifluoroacetic acid. Stirred at room temperature for one hour.Concentrated off volatiles, azeotroped with toluene to give crude.Triturated twice with 1:1 diethyl ether/hexanes to give thetrifluoroacetate salt of 3-amino-pyrrolidine-1-carboxylic acid7-(4-fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-5-ylester 226 (0.0057 g, 0.0104 mmol, 68%.) ¹H NMR (CD₃SOCD₃) δ 9.00 (s,1H), 8.41 (s, 1H), 8.21 (s, 1H), 7.76 (dd, 1H), 7.36 (dd, 2H), 7.22 (dd,2H), 4.72 (s, 2H), 4.36 (s, 2H), 3.93-3.35 (m, 7H) ¹⁹F NMR: −73.9 MS:437 (M+1), 435 (M−1)

Example 227

2-Amino-1,2,4 thiadiazole (0.006 g, 0.06 mmol) and triethylamine (0.0376mL, 0.27 mmol) were added to 1 mL dichloromethane and cooled to 0° C. Tothis was slowly added chlorosulfonylisocyanate (0.007 mL, 0.08 mmol) at0° C. Stirred thirty minutes until starting material consumed.Simultaneously, in a separate flask trimethylsilylethyl ether 44 wasdissolved in 0.5 mL tetrahydrofuran. To this was added triethylamine(0.0376 mL, 0.27 mmol) and 1M tetrabutylammonium fluoride intetrahydrofuran (0.135, 0.135 mmol) and stirred at room temperature.After 20 minutes, diluted with dichloromethane, washed with 1M HClsolution and brine, concentrated to give crude. At 0° C., dissolved in0.5 mL dichloromethane and added to the solution prepared in situ above.Stirred at 0° C. for 5 minutes, catalytic DMAP added, then stirred forone hour at room temperature. Diluted with dichloromethane, washed with1M HCl solution, brine, concentrated to give crude. Chromatographed (5to 30% methanol/dichloromethane) to give dimethylaminopyridine adduct227 (0.033 g, 0.046 mmol, 68%.) ¹H NMR (CDCl₃) δ 8.97 (dd, 1H), 8.54 (d,2H), 8.19 (d, 1H), 8.00 (s, 1H), 7.72 (d, 4H), 7.42 (dd, 1H), 7.26-7.14(m, 7H), 7.02 (dd, 2H), 6.52 (d, 2H), 4.74 (s, 2H), 4.17 (s, 2H), 3.22(s, 6H.) MS: 718 (M+1).

Example 228

Carbamate 227 (0.007 gm, 0.0097 mmol) was dissolved in 0.25 mL ofdichloromethane. To is was added 0.1 mL of triethylsilane and 0.05 mL oftrifluoroacetic acid. Stirred at room temperature and after ten minutescomplete by TLC. Concentrated off volatiles, azeotroped with toluene togive crude. Triturated twice with 1:1 diethyl ether/hexanes to give 228(0.004 g, 0.0073 mmol, 75%.) ¹H NMR (CD₃SOCD₃) δ 9.22 (d, 1H), 9.09 (s,1H), 8.47 (s, 1H), 8.19 (s, 1H), 8.01 (s, 1H), 7.37 (s, 2H), 7.19 (s,1H), 6.96 (s, 2H), 4.76 (s, 2H), 4.45 (s, 2H), 3.21 (d, 6H.) ¹⁹F NMR:−75.95 MS: 552 (M+1), 550 (M−1)

Example 229

Carboxylic acid 213 (0.015 g, 0.029 mmol) was dissolved in 0.8 mL ofdimethylformamide. To this was added BOC-piperazine (0.0116 g, 0.058mmol), triethylamine (0.012 mL, 0.087 mmol),1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.011 g,0.058 mmol), 1-Hydroxybenzotriazole hydrate (0.0059 g, 0.0435 mmol) andstirred at room temperature. After 15 hours, starting material wasconsumed. Dilute with dichloromethane, washed with 1M HCl solution,saturated brine solution, dried (Na₂SO₄), concentrated to give crudeproduct. Chromatographed (10 to 50% ethyl acetate/hexanes) to give4-[9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-5-carbonyl]-piperazine-1-carboxylicacid tert-butyl ester 229 (0.009 g, 0.013 mmol, 45%.) ¹H NMR (CDCl₃)9.075 (s, 1H), 8.15 (s, 1H), 8.03 (d, 1H), 7.74 (dd, 4H), 7.53 (dd, 1H),7.27 (m, 8H), 7.04 (dd, 2H), 4.91 (d, J=17 Hz, 1H), 4.69 (d, J=17Hz,1H), 4.41 (d, J=17 Hz, 1H), 4.055 (d, J=17 Hz, 1H), 3.55-2.96 (br m, 8H), 1.44 (s, 9H.) MS: 687 (M+1).

Example 230

Carboxamide 229 (0.0108 g, 0.0153 mmol) was dissolved in 1 mL ofdichloromethane. To this was added 0.4 mL of triethylsilane and 0.2 mLof trifluoroacetic acid. Stirred at room temperature and after tenminutes complete by TLC. Concentrated off volatiles, azeotroped withtoluene to give crude. Then dissolved in 0.6 mL dichloromethane, 0.6 mltrifluoroacetic acid. Stirred at room temperature for one hour.Concentrated off volatiles, azeotroped with toluene to give crude.Triturated twice with 1:1 diethyl ether/hexanes to give7-(4-fluoro-benzyl)-9-hydroxy-5-(piperazine-1-carbonyl)-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one230 (0.039 g, 0.0682 mmol, 100%.) ¹H NMR (CD₃SOCD₃) δ 98.97 (s, 2H),8.32 (d, 1H), 7.74 (s, 1H), 7.36 (dd, 2H), 7.19 (dd, 2H), 4.86 (d, 1H),4.58 (d, 1H), 4.42 (d, 1H), 4.34 (d, 1H), 3.9-2.90 (m, 8H.) ¹⁹F NMR:−74.202 MS: 421 (M+1), 419 (M−1)

Example 231

Carboxylic acid 213 (0.010 g, 0.0193 mmol) was dissolved in 0.3 mL ofdimethylformamide. To this was added 2-aminomethylpyridine (0.004 g,0.0386 mmol), triethylamine (0.008 mL, 0.058 mmol),1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.074 g,0.0386 mmol), 1-Hydroxybenzotriazole hydrate (0.0039 g, 0.029 mmol) andstirred at room temperature. After 15 hours, starting material wasconsumed. Dilute with dichloromethane, washed with 1M HCl solution,saturated brine solution, dried (Na₂SO₄), concentrated to give crudeproduct. Chromatographed (0 to 8% methanol/dichloromethane) to give9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-5-carboxylicacid (pyridin-2-ylmethyl)-amide 231 (0.007 g, 0.011 mmol, 59%.) ¹H NMR(CDCl₃) 8.94 (s, 1H), 8.45 (d, 2H), 8.05 (s, 1H), 7.70 (d, 4H),7.57-7.17 (m, 12H), 7.05 (d, 2H), 4.78 (s, 1H), 4.69 (d, J=5Hz, 1H),4.38 (s, 1H). MS: 609 (M+1).

Example 232

Carboxamide 231 (0.225 g, 0.355 mmol) was dissolved in 1 mL ofdichloromethane. To this was added 0.5 mL of triethylsilane and 0.25 mLof trifluoroacetic acid. Stirred at room temperature and after tenminutes complete by TLC. Concentrated off volatiles, azeotroped withtoluene to give crude. Triturated twice with 1:1 diethyl ether/hexanesto give7-(4-fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-5-carboxylicacid (pyridin-2-ylmethyl)-amide 232 (0.11 g, 0.20 mmol, 56%.) ¹H NMR(CD₃SOCD₃) δ 9.18 (s, 1H), 8.96 (d, 1H), 8.65 (dd, 2H), 8.09 (dd, 1H),7.76 (dd, 1H), 7.64 (dd, 1H), 7.36 (dd, 2H), 7.22 (dd, 2H), 4.70 (S,4H), 4.54 (s, 2H). ¹⁹F NMR: −75.37 MS: 443 (M+1), 441 (M−1)

Example 233

Carboxylic acid 213 (0.010 g, 0.0193 mmol) was dissolved in 0.3 mL ofdimethylformamide. To this was added 4-aminomethylpyridine (0.004 mL,0.0386 mmol), triethylamine (0.008 mL, 0.058 mmol),1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.074 g,0.0386 mmol), 1-Hydroxybenzotriazole hydrate (0.0039 g, 0.029 mmol) andstirred at room temperature. After 15 hours, starting material wasconsumed. Dilute with dichloromethane, washed with 1M HCl solution,saturated brine solution, dried (Na₂SO₄), concentrated to give crudeproduct. Chromatographed (0 to 8% methanol/dichloromethane) to give 233(0.0048 g, 0.008 mmol, 41%.) ¹H NMR (CDCl₃) δ 8.71 (s, 1H), 8.66 (d,2H), 7.99 (dd, 2H), 7.65 (s, 1H), 7.51 (s, 4H), 7.34 (m, 9H), 7.05 (dd,2H), 4.69 (s, 2H), 4.25 (d, 2H), 4.00 (s, 2H). MS: 609 (M+1).

Example 234

Carboxamide 233 (0.137 g, 0.225 mmol) was dissolved in 1 mL ofdichloromethane. To this was added 0.5 mL of triethylsilane and 0.25 mLof trifluoroacetic acid. Stirred at room temperature and after tenminutes complete by TLC. Concentrated off volatiles, azeotroped withtoluene to give crude. Triturated twice with 1:1 diethyl ether/hexanesto give7-(4-fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-5-carboxylicacid (pyridin-4-ylmethyl)-amide 234 (0.114 g, 0.20 mmol, 91%.) ¹H NMR(CD₃SOCD₃) δ 9.24 (dd, 1H), 8.98 (d, 1H), 8.77 (dd, 2H), 8.53 (d, 1H),7.79 (dd, 3H), 7.40 (dd, 2H), 7.23 (dd, 2H), 4.71 (s, 4H), 4.56 (s, 2H).¹⁹F NMR: −74.906 MS: 443 (M+1), 441 (M−1)

Example 235

Carboxylic acid 213 (0.020 g, 0.0386 mmol) was dissolved in 0.4 mL ofdimethylformamide. To this was added methyl piperazine (0.0085 mL, 0.077mmol), diisopropylethylamine (0.027 mL, 0.154 mmol),O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (0.029 g, 0.0777 mmol) and stirred at roomtemperature. After 15 hours, starting material was consumed. Dilute withdichloromethane, washed with saturated brine solution, dried (Na₂SO₄),concentrated to give crude product. Chromatographed (0 to 8%methanol/dichloromethane) to give 235 (0.017 g, 0.028 mmol, 73%.) ¹H NMR(CDCl₃) δ 9.06 (dd, 1H), 8.13 (s, 1H), 8.05 (dd, 1H), 7.76 (dd, 4H),7.53 (dd, 1H), 7.27 (m, 8H), 7.06 (dd, 2H), 4.93 (d, J=15 Hz, 1H), 4.72(d, J=15 Hz, 1H), 4.36 (d, J=15 Hz, 1H), 4.066 (d, J=15 Hz, 1H),3.88-2.97 (m, 8H), 2.28 (s, 3H.) MS: 601 (M+1).

Example 236

Carboxamide 235 (0.015 g, 0.025 mmol) was dissolved in 0.5 mL ofdichloromethane. To this was added 0.2 mL of triethylsilane and 0.1 mLof trifluoroacetic acid. Stirred at room temperature and after tenminutes complete by TLC. Concentrated off volatiles, azeotroped withtoluene to give crude. Triturated twice with 1:1 diethyl ether/hexanesto give7-(4-fluoro-benzyl)-9-hydroxy-5-(4-methyl-piperazine-1-carbonyl)-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one236 (0.0135 g, 0.227 mmol, 91%.) ¹H NMR 90 0° C.(CD₃SOCD₃) δ 8.98 (dd,1H), 8.28 (d, 1H), 7.74 (dd, 1H), 7.40 (dd, 2H), 7.21 (dd, 2H), 4.72 (s,4H), 4.40 (s, 4H), 3.5 (br s, 4H), 2.81 (s, 3H.) ¹⁹F NMR: −74.688 MS:436 (M+1), 434 (M−1)

Example 237

Carboxylic acid 213 (0.10 g, 0.193 mmol) was dissolved in 2 mL ofdimethylformamide. To this was added morpholine (0.0337 mL, 0.386 mmol),diisopropylethylamine (0.135 mL, 0.772 mmol),O-(7-azabenzotiazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU, 0.146 g, 0.386 mmol) and stirred at roomtemperature. After 15 hours, starting material was consumed. Dilute withdichloromethane, washed with 1M HCl solution, saturated brine solution,dried (Na₂SO₄), concentrated to give crude product. Chromatographed (0to 5% methanol/dichloromethane) to give pure product (0.06 g, 0.102mmol, 53%.) ¹H NMR (CDCl₃) δ 9.08 (dd, 1H), 8.15 (s, 1H), 8.06 (dd, 1H),7.76 (dd, 4H), 7.55 (dd, 1H), 7.30 (m, 8H), 7.07 (dd, 2H), 4.95 (d, J=15Hz, 1H), 4.70 (d, J=15 Hz, 1H), 4.42 (d, J=15 Hz, 1H), 4.14 (d, J=15 Hz,1H), 3.94-3.79 (m, 4H), 3.41 (m, 2H), 2.99 (m, 2H.) MS: 588 (M+1).

Example 238

Carboxamide 237 (0.06 g, 0.102 mmol) was dissolved in 1 mL ofdichloromethane. To this was added 0.4 mL of triethylsilane and 0.2 mLof trifluoroacetic acid. Stirred at room temperature and after tenminutes complete by TLC. Concentrated off volatiles, azeotroped withtoluene to give crude. Triturated twice with 1:1 diethyl ether/hexanesto give7-(4fluoro-benzyl)-9-hydroxy-5-(morpholine-4-carbonyl)-6,7dihydro-pyrrolo[3,4-g]quinolin-8-one238 (0.0459 g, 0.109 mmol, 100%.) ¹H NMR (CDCl₃) δ 9.05 (dd, 1H), 8.20(d, 1H), 7.64 (dd, 1H), 7.35 (m, 2H), 7.08 (dd, 2H), 4.91 (d, J=15 Hz,1H), 4.68 (d, J=15 Hz, 1H), 4.59 (d, J=15 Hz, 1 Hz), 4.24 (d, J=15 Hz,1H), 3.99 (m, 3H), 3.5 (s, 2H), 3.18 (s, 2H.) MS: 436 (M+1), 434 (M−1)

Example 239

Carboxylic acid 213 (0.018 g, 0.0347 mmol) was dissolved in 0.5 mL ofdimethylformamide. To this was added piperidine (0.0068 mL, 0.0695mmol), diisopropylethylamine (0.024 mL, 0.1399 mmol), HATU (0.027 g,0.0695 mmol) and stirred at room temperature. After 2.5 hours, startingmaterial was consumed. Dilute with ethyl acetate, washed with 2.5% LiClsolution, saturated brine solution, dried (Na₂SO₄), concentrated to givecrude 239. ¹H NMR (CDCl₃) δ 9.04 (dd, 1H), 8.12 (s, 1H), 8.06 (d, 1H),7.75 (dd, 4H), 7.52 (dd, 1H), 7.30 (m, 8H), 7.06 (dd, 2H), 4.94 (d, J=15Hz, 1H), 4.69 (d, J=15 Hz, 1H), 4.40 (d, J=15 Hz, 1H), 4.07 (d, J=15 Hz,1H), 3.91 (s, 1H), 3.71 (s, 1H), 3.28 (s, 1H), 3.18 (s, 1H), 2.0-1.28(m, 6H.) MS: 586 (M+1).

Example 240

Carboxamide 239 (crude) was dissolved in 0.5 mL of dichloromethane. Tothis was added 0.2 mL of triethylsilane and 0.1 mL of trifluoroaceticacid. Stirred at room temperature and after ten minutes complete by TLC.Concentrated off volatiles, azeotroped with toluene to give crude.Triturated twice with 1:1 diethyl ether/hexanes to give7-(4-fluoro-benzyl)-9-hydroxy-5-piperidine-1-carbonyl)-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one240 (0.0084 g, 0.02 mmol, 58% for 2 steps.) ¹H NMR (CDCl₃) δ 8.97 (dd,1H), 8.17 (d, 1H), 7.60 (dd, 1H), 7.34 (dd, 2H), 7.07 (dd, 2H), 4.91 (d,J=15 Hz, 1H), 4.66 (d, J=15 Hz, 1H), 4.56 (d, J=15 Hz, 1 Hz), 4.22 (d,J=15 Hz, 1H), 3.91 (s, 1H), 3.75 (s, 1H), 3.11 (s, 2H), 1.7-1.3 (m, 6H.)MS: 420 (M+1), 418 (M−1)

Example 241

To a mixture of pyrazine-2,3-dicarboxylic acid (20 g, 119 mmol, 1equiv.) was added MeOH (80 mL) followed by dropwise addition ofconcentrated H₂SO₄ (36 mL, 680 mmol, 5.7 equiv.) over 45 minutes. Thismethod is similar to that that cited for a different substrate (J. Am.Chem. Soc., 73, 1951, 5614-5616). The reaction was heated at 75° C. for16 hours and then cooled and quenched with water (200 mL). It wasextracted with EtOAc (4×60 mL) and the organic layer washed severaltimes with water (3×50 ml), saturated NaHCO₃ (50 ml), brine solution (50mL). It was dried over Na₂SO₄, filtered and concentrated in vacuo toyield pyrazine-2,3-dicarboxylic acid methyl ester 241 as a brown solid(47%, 10.97 g, 55.9 mmol). ¹H NMR (300 MHz) CDCl₃ δ 8.79 (d, J=2.7 Hz, 2H), 4.05 (s, 3 H), 4.04 (s, 3 H). TLC Rf: 0.7 ethyl acetate/methanol(9/1)

Example 242

Into a flask containing pyrazine-2,3-dicarboxylic acid methyl ester 241(10.70 g, 54.6 mmol, 1 equiv.) was added THF (150 mL) under a nitrogenatmosphere followed by 1-(4-Fluoro-benzyl)-pyrrolidine-2,5-dione 1(11.30 g, 54.6 mmol, 1 equiv.). MeOH (1.8 mL) was then added and at 0°C. was added NaH (4.8 g, 120.1 mmol, 2.2 equiv.) carefully in fourportions. Refluxing was carried out for 20 hours after which thereaction was cooled and placed in a 0° C. icebath. HCl (6 N, 30 mL, H₂O)was slowly added while vigorously stirring. The resulting solid wasfiltered, and washed thoroughly with water followed by ether. It wasthen dried in a vacuum oven (60° C., 12 hours) to realize 8.7 gm (47%,25.66 mmol) of7-(4-fluoro-benzyl)-5,9-dihydroxy-pyrrolo[3,4-g]quinoxaline-6,8-dione242. ¹H NMR (300 MHz) CDCl₃ δ 7.15-7.33 (m, 5 H), 5.91 (s, 2 H), 3.96(s, 3 H), 3.88 (s, 3 H). MS: 340.3 (M+1).

Example 243

7-(4-Fluoro-benzyl)-5,9-dihydroxy-pyrrolo [3,4-g] quinoxaline-6,8-dione242 (1 g, 2.95 mmol, 1 equiv.) was dissolved in DMF (30 ml, 0.11 M) andpyridine (477 μL, 5.89 mmol, 2 equiv.) before ethyl chloroformate wasadded (237 μL, 2.95 mmol, 1 equiv.). The reaction was stirred for 16hours before being quenched with HCl (30 ml, 1 N) and extracted withethyl acetate (2×30 mL). The organic layer washed several times withwater (4×30 mL), saturated NaHCO₃ (50 mL), brine solution (50 mL). Itwas dried over Na₂SO₄, filtered and concentrated in vacuo.Recrystallization was carried out in ethyl acetate and Hexanes to yieldcarbonic acid ethyl ester7-(4-fluoro-benzyl)-9-hydroxy-6,8-dioxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoxalin-5-ylester 243 as a light brown solid (98%, 1.20 g, 2.89 mmol). ¹H NMR (300MHz) CDCl₃ δ 9.09 (d, J=6 Hz, 1 H), 8.97 (d, J=6 Hz, 1 H), 8.65 (bs, 1H), 7.46 (d, J=4.8 Hz, 2 H), 7.03 (d, J=4.8 Hz, 2 H), 4.85 (s, 2 H),4.04 (q, J=2.8 Hz, 2 H), 1.43 (q, J=2.8 Hz, 3 H). MS: 412.6 (M+1).

Example 244

Carbonic acidmono-[1-(1-benzyl-4-methylene-2,5-dioxo-pyrrolidin-3-ylidene)-ethyl]ester 243 (1.1 g, 2.68 mmol, 1 equiv.) was dissolved in 1,2dichloroethane (50 mL, 0.055 M) and to this was addeddiphenyldiazomethane (1.05 g, 5.35 mmol, 2 equiv.) and heated at 70° C.under a nitrogen atmosphere for 24 hours. The reaction was concentratedin vacuo and purified by silica gel chromatography using 4/1Hexanes/Ethyl acetate to obtain carbonic acid9-benzhydryloxy-7-(4-fluoro-benzyl)-6,8-dioxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoxalin-5-ylethyl ester 244 (70%, 1085 mg, 1.87 mmol). ¹H NMR (300 MHz) CDCl₃ δ 9.09(d, J=6 Hz, 1 H), 8.97 (d, J=6 Hz, 1 H), 8.65 (bs, 1 H), 7.46 (d, J=4.8Hz, 2 H), 7.03 (d, J=4.8 Hz, 2 H), 4.85 (s, 2 H), 4.04 (q, J=2.8 Hz, 2H), 1.43 (q, J=2.8 Hz, 3 H). MS: 600.2 (M+23). TLC R_(f): 0.3Hexanes/Ethyl acetate (7/3)

Example 245

Carbonic acid9-benzhydryloxy-7-(4-fluoro-benzyl)-6,8-dioxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoxalin-5-ylester ethyl ester 244 (500 mg, 0.87 mmol) was dissolved in THE (9 mL,0.1 M) along with DMAP (211 mg, 1.73 mmol, 2 equiv.). A solution ofK₂CO₃ (1.20 g, 8.66 mmol, and 10 equiv.) was dissolved separately in H₂O(6 mL) before being transferred to the reaction mixture. The reactionwas allowed to stir for 18 hours and quenched with HCl (20 mL, 1 N) andextracted with ethyl acetate (2×30 mL). The organic layer was washedwith saturated NH₄Cl solution (25 mL), brine solution (25 mL) and driedover Na₂SO₄ and concentrated in vacuo to yield5-benzhydryloxy-7-(4-fluoro-benzyl)-9-hydroxy-pyrrolo[3,4-g]quinoxaline-6,8-dione245 (94%, 413 mg, 0.82 mmol).

¹H NMR (300 MHz) CDCl₃ δ 9.08 (d, J=1.5 Hz, 1 H), 8.92 (d, J=1.5 Hz, 1H), 7.67 (s, 1 H), 7.67-7.42 (dd, J₁=1.5 Hz, J₂=8.4 Hz, 4 H), 7.43-7.48(m, 2 H), 7.19-7.27 (m, 7 H), 7.03-7.20 (m, 1 H), 4.86 (s, 2 H). MS:528.0 (M+23). TLC R_(f): 0.2 Hexanes/Ethyl acetate (8/2)

Example 246

Into a flask containing5-benzhydryloxy-7-(4-fluoro-benzyl)-9-hydroxy-pyrrolo[3,4-g]quinoxaline-6,8-dione245 (350 mg, 0.69 mmol, 1 equiv.) was added DMF (20 mL) followed byK₂CO₃ (478 mg, 3.46 mmol, 5 equiv.). To this was added MeI (983 μL, 6.93mmol, 10 equiv.) under a nitrogen atmosphere and stirred for 16 hours.To the reaction was then added water (50 mL) and extracted with ethylacetate (2×40 mL). The organic layer was washed several times with water(3×30 mL), saturated NaHCO₃ (40 mL), brine solution (30 mL). It wasdried over Na₂SO₄, filtered and concentrated in vacuo before beingpurified by silica gel chromatography using 3/2 Hexanes/ethyl acetate toobtain5-benzhydryloxy-7-(4-fluoro-benzyl)-9-methoxy-pyrrolo[3,4-g]quinoxaline-6,8-dione246 (78%, 280 mg, 0.54 mmol) as a yellow solid, ¹H NMR (300 MHz) CDCl₃ δ9.03 (d, J=1.5 Hz, 1 H), 8.97 (d, J=1.5 Hz, 1 H), 7.75 (s, 1 H), 7.60(dd, J₁=1.5 Hz, J₂=8.4 Hz, 4 H), 7.43-7.48 (m, 2 H), 7.19-7.27 (m, 7 H),7.03-7.20 (m, 1 H), 4.86 (s, 2 H), 4.37 (s, 3 H). MS: 542.0 (M+23). TLCR_(f): 0.5 Hexanes/Ethyl acetate (1/1)

Example 247

5-Benzhydryloxy-7-(4-fluoro-benzyl)-9-methoxy-pyrrolo[3,4-g]quinoxaline-6,8-dione246 (10 mg, 0.019 mmol, 1 equiv.) was dissolved in CH₂Cl₂ (0.2 mL) andMeOH (0.5 mL) under a nitrogen atmosphere at 0° C. Sodium borohydride(NaBH₄) was added (115 μL, 0.057 mmol, 3 equiv., 0.5 M). The reactionwas allowed to stir for 1 hour and then quenched with water (5 mL) andextracted with ethyl acetate (2×5 mL). The organic layer was washedseveral times with water (2×10 mL), brine solution (10 mL). It was driedover Na₂SO₄, filtered and concentrated in vacuo and purified bypreparatory thin-layer chromatography (PTLC) using 3/2 Hexanes/Ethylacetate to obtain5-benzhydryloxy-7-(4-fluoro-benzyl)-8-hydroxy-9-methoxy-7,8-dihydro-pyrrolo[3,4-g]quinoxalin-6-one247a (34%, 3 mg) and reduced species:5-benzhydryloxy-7-(4-fluoro-benzyl)-8-hydroxy-9-methoxy-1,2,3,4,7,8-hexahydro-pyrrolo[3,4-g]quinoxalin-6-one247b (21%, 2 mg) and5-benzhydryloxy-7-(4-fluoro-benzyl)-9-methoxy-1,2,3,4tetrahydro-pyrrolo3,4-g]quinoxaline-6,8-dione 247c (34%, 3.4 mg).

247a: ¹H NMR (300 MHz) CDCl₃ δ 8.86 (d, J=1.8 Hz, 1 H), 8.82 (d, J=1.8Hz, 1 H), 7.69 (s, 1 H), 7.69-7.56 (m, 1 H), 7.54-7.56 (m, 1 H),7.16-7.32 (m, 10 H), 7.01-7.17 (s, 2 H), 5.78 (bs, 1 H), 5.18 (d, J=14.7Hz, 1 H), 4.38 (d, J=13.5 Hz, 1 H), 4.18 (s, 3 H), 3.83 (s, 2 H). MS:544.0(M+23). TLC R_(f): 0.3 Hexanes/Ethyl acetate (3/2)

247b: ¹H NMR (300 MHz) CDCl₃ δ 7.27-7.7.40 (m, 12 H), 6.95-7.01 (m, 2H), 4.70 (s, 2 H), 4.01 (s, 3 H), 3.32 (t, J=3.9 Hz, 2 H), 3.13 (t,J=5.1 Hz, 2 H), 2.75 (s, 2 H). MS: 545.9 (M+23). TLC R_(f): 0.25Hexanes/Ethyl acetate (1/1)

247c: ¹H NMR (300 MHz) CDCl₃ δ 7.27-7.7.40 (m, 12 H), 5.58 (bs, 1 H),5.01 (d, J=14.1 Hz, 1 H), 4.21 (d, J=9.6 Hz, 1 H), 3.85 (s, 3 H),3.32-3.45 (m, 2 H), 3.02-3.05 (t, J=5.1 Hz, 2 H), 1.63 (bs, 2 H). R_(f):0.2 Hexanes/Ethyl acetate (1/1)

Example 248

Into a flask containing5-benzhydryloxy-7-(4-fluoro-benzyl)-8-hydroxy-9-methoxy-7,8-dihydro-pyrrolo[3,4-g]quinoxalin-6-one247a (20 mg, 0.038 mmol, 1 equiv.) was added CH₂Cl₂ (1 mL) under anitrogen atmosphere. Triethylsilane (200 μL) was added followed bytrifluoroacetic acid (200 μL). The reaction was allowed to stir for 1hour and then concentrated in vacuo until thoroughly dried. To the oilwas Hexanes/Ethyl ether (15 mL, 1/1 ratio) and sonicated. The resultingsolid was then filtered, washed in hexanes, and air dried to give7-(4-fluoro-benzyl)-5-hydroxy-9-methoxy-7,8-dihydro-pyrrolo[3,4-g]quinoxalin-6-one248 (38%, 7.2 mg, 0.0.14 mmol). ¹H NMR (300 MHz) CDCl₃ δ 8.95 (d, J=13.8Hz, 2 H), 7.23-7.27 (m, 2 H), 6.96-7.05 (s, 2 H), 4.79 (2 H), 4.55 (s, 2H), 4.14 (s, 3 H). ¹⁹F NMR (300 MHz) CDCl₃ δ 62.80. MS: 340.1 (M+1)

Example 249

Into a flask containing5-benzhydryloxy-7-(4-fluoro-benzyl)-9-methoxy-pyrrolo[3,4-g]quinoxaline-6,8-dione246 (10 mg, 0.019 mmol, 1 equiv.) was added CH₂Cl₂ (1 mL) and under anitrogen atmosphere was added triethylsilane (200 μL) followed bytrifluoroacetic acid (200 μL). The reaction was allowed to stir for 1.5hours and concentrated in vacuo until thoroughly dried. To the oil wasadded Hexanes/Ethyl ether (20 mL, 1/1 ratio) and sonicated. Theresulting solid was filtered, washed in hexanes and air dried to give7-(4-fluoro-benzyl)-5-hydroxy-9-methoxy-pyrrolo[3,4-g]quinoxaline-6,8-dione249 (67%, 4.6 mg, 0.015 mmol). ¹H NMR (300 MHz) CDCl₃ δ 9.07 (d, J=1.8Hz 1 H), 8.97 (d, J=1.8 Hz, 1 H), 7.23-7.27 (m, 2 H), 6.96-7.05 (s, 2H), 4.87 (s, 2 H), 4.46 (s, 3 H). ¹⁹F NMR (300 MHz) CDCl₃ δ 62.77 MS:354.0 (M+1)

Example 250

To commercially available, 1-benzyl-1H-[1,2,3]triazole-4,5-dicarboxylicacid (4.5 g, 18.2 mmol, 1 equiv.) was added MeOH (30 mL) followed bydropwise addition of H₂SO₄ (5.5 mL, 103.75 mmol, 5.7 equiv.) over 20minutes by a method similar to J. Am. Chem. Soc., 73, 1951, 5614-5616.The reaction was heated at 85° C. for 2 h. The reaction was cooled andquenched with water (100 mL). It was extracted with ethyl acetate (4×40mL) and the organic layer washed several times with water (3×50 mL),saturated NaHCO₃ (50 mL), brine solution (50 mL). It was dried overNa₂SO₄, filtered and concentrated in vacuo to yield1-Benzyl-1H-[1,2,3]triazole-4,5-dicarboxylic acid dimethyl ester 250 asa brown solid (76%, 3.85 g, 55.9 mmol). ¹H NMR (300 MHz) CDCl₃δ7.15-7.33 (m, 5 H), 5.41 (s, 2 H), 3.92 (s, 3 H), 3.84 (s, 3 H).

Example 251

Into a flask containing 1-benzyl-1H-[1,2,3]triazole-4,5-dicarboxylicacid dimethyl ester 250 (3.75 g, 13.64 mmol, 1 equiv.) was added THF(150 mL) under a nitrogen followed by1-(4-fluoro-benzyl)-pyrrolidine-2,5-dione 1 (2.82 g, 13.64 mmol, 1equiv.). Methanol (MeOH, 1.1 mL) was added and at 0° C. was added NaH(1.20 g, 29.99 mmol, 2.2 equiv., 60% dispersion) carefully in fourportions. Refluxing was carried out for 20 hours after which thereaction was cooled and placed in a 0° C. icebath. HCl (6 N, 20 mL, H₂O)was slowly added while vigorously stirring. The resulting solid wasfiltered, and washed thoroughly with water followed by ether. It wasthen dried in a vacuum oven (60° C., overnight) to realize 3.34 gm (60%,8.18 mmol) of1-benzyl-6-(4-fluoro-benzyl)-4,8-dihydroxy-1H-pyrrolo[3′,4′:4,5]benzo[1,2-d][1,2,3]triazole-5,7-dione251. ¹H NMR (300 MHz) CD₃OD δ 9.51 (b, 1 H), 7.45-7.35 (m, 8 H),7.15-7.33 (m, 2 H), 5.92 (s, 2 H), 4.78 (s, 2 H).

Example 252

1H-Imidazole-4,5-dicarboxylic acid dimethyl ester (2 g, 10.87 mmol, 1equiv.) was dissolved in THF (55 mL, 0.2 M) and DMAP (1.46 g, 11.95mmol, 1.1 equiv.) before Di-tert-butyl dicarbonate (3.50 g, 16.29 mmol,1.4 equiv.) was added. The reaction was stirred for 16 hours beforebeing quenched with saturated NH₄Cl (30 mL) and extracted with ethylacetate (2×30 mL) and the organic layer washed several times with water(4×30 mL), brine solution (50 mL). It was dried over Na₂SO₄, filteredand concentrated in vacuo. Imidazole-1,4,5-tricarboxylic acid1-tert-butyl ester 4,5-dimethyl ester 252 (3.85 g, 100%, 10.87 mmol). ¹HNMR (300 MHz) CDCl₃ δ 8.02 (s, 1 H), 3.99 (s, 3 H), 3.92 (s, 3 H). MS:306.8 (M+23). TLC R_(f): 0.6 Hexanes/Ethyl acetate (1/1)

Example 253

Into a flask containing imidazole-1,4,5-tricarboxylic acid 1-tert-butylester 4,5-dimethyl ester 252 (3.85 g, 13.55 mmol, 1 equiv.) was addedTHF (55 mL) under a nitrogen atmosphere followed by1-(4-fluoro-benzyl)-pyrrolidine-2,5-dione 1(2.80 g, 13.55 mmol, 1equiv.). MeOH (0.4 mL) was added and at 0° C. was added NaH (1.20 g,29.81 mmol, 2.2 equiv., 60% dispersion) carefully in four portions.Refluxing was carried out for 20 hours after which the reaction wascooled and placed in a 0° C. icebath. HCl (6 N, 30 mL, H₂O) was slowlyadded while vigorously stirring. The resulting solid was filtered, andwashed thoroughly with water followed by ether. It was then dried in avacuum oven (60° C., overnight) to realize 2.70 gm of a crude solidwhich was recrystallized with dioxane (650 mL).6-(4-fluoro-benzyl)-4,8-dihydroxy-1H-1,3,6-triaza-s-indacene-5,7-dione253 1.65 g, 5.01 mmol). ¹H NMR (300 MHz) DMSO d₆ δ 8.64 (s, 1 H),7.25-7.35 (m, 2 H), 7.10-7.29 (m, 2 H), 4.66 (s, 2 H). ¹⁹F NMR (300 MHz)CDCl₃ δ 61.34. MS: 328.1 (M+1)

Example 254

1H-Imidazole-4,5-dicarboxylic acid dimethyl ester (1.5 g, 8.15 mmol, 1equiv.) was dissolved in MeOH (10 mL) and benzyl bromide (1.16 mL, 9.77mmol, 1.1 equiv.) before sodium hydride (360 mg, 1.1 equiv., 60%dispersion) and sodium iodide (200 mg) was added. The reaction wasstirred for 16 hours before being quenched with saturated NH₄Cl (30 mL)and extracted with ethyl acetate (2×30 mL) and the organic layer washedseveral times with water (4×30 mL), brine solution (50 mL). It was driedover Na₂SO₄, filtered and concentrated in vacuo.1-Benzyl-1H-imidazole-4,5-dicarboxylic acid dimethyl ester 254 (2.01 g,90%, 7.33 mmol). ¹H NMR (300 MHz) CDCl₃ δ 7.58 (s, 1 H), 7.33-7.42 (m, 3H), 7.14-7.18 (m, 2 H), 5.41 (s, 2 H), 3.92 (s, 3 H), 3.84 (s, 3 H). MS:275.1 (M+1)

Example 255

Into a flask containing 1-benzyl-1H-imidazole-4,5-dicarboxylic aciddimethyl ester 254 (2.80 g, 10.22 mmol, 1 equiv.) was added THF (35 mL)under a nitrogen atmosphere followed by1-(4-Fluoro-benzyl)-pyrrolidine-2,5-dione 1 (2.2 g, 10.22 mmol, 1equiv.). MeOH (0.5 mL) was then added and at 0° C. was added NaH (940mg, 23.49 mmol, 2.2 equiv.) carefully in four portions. Refluxing wascarried out for 20 hours after which the reaction was cooled and placedin a 0° C. icebath. HCl (6 N, 30 mL, H₂O) was slowly added whilevigorously stirring. The resulting solid was filtered, and washedthoroughly with water followed by ether. It was then dried in a vacuumoven (60° C., 12 hours) to realize 4.20 gm of a crude solid. It wasrecrystallized with dioxane (700 ml) to realize1-benzyl-6-(4-fluoro-benzyl)-4,8-dihydroxy-1H-1,3,6-triaza-s-indacene-5,7-dione255 (1.74 g, 41%, 4.19 mmol). ¹H NMR (300 MHz) DMSO d₆ δ 10.40 (bs, 1H), 8.73 (s, 1 H), 7.22-7.7.43 (m, 3 H), 7.05-7.18 (m, 2 H), 5.65 (s, 2H), 4.60 (s, 2 H). MS: 418.1 (M+1).

Example 256

1-Benzyl-6-(4-fluoro-benzyl)-4,8-dihydroxy-1H-1,3,6-triaza-s-indacene-5,7-dione255 (1 g, 2.39 mmol, 1 equiv.) was dissolved in a flask containing DMF(24 mL, 0.1 M) and pyridine (290 μL, 2.88 mmol, 1.5 equiv.). Ethylchloroformate was added (231 μL, 2.88 mmol, 1.2 equiv.) under a nitrogenatmosphere. The reaction was stirred for 16 hours before being quenchedwith saturated NH₄Cl (30 mL) and extracted with ethyl acetate (2×30 mL)and the organic layer washed several times with water (4×30 mL),saturated NaHCO₃ (50 mL), brine solution (50 mL). It was dried overNa₂SO₄, filtered and concentrated in vacuo. Trituration was carried outwith Hexanes/Ethyl acetate (1/4, 100 mL) to remove the correspondingbiscarbonate to give carbonic acid3-benzyl-6-(4-fluoro-benzyl)-8-hydroxy-5,7-dioxo-3,5,6,7-tetrahydro-1,3,6-triaza-s-indacen-4-ylester ethyl ester 256 (13%, 145 mg, 0.296 mmol). ¹H NMR (300 MHz) DMSOd₆ δ 8.63 (s, 1 H), 7.45-7.35 (m, 6 H), 7.15-7.33 (m, 4H), 5.59 (s, 2H),4.63 (s, 2 H), 3.98 (q, J=6.9 Hz, 2 H), 1.17 (t, J=6.9 Hz, 3 H). MS:490.2 (M+1). TLC R_(f): 0.6 Ethyl acetate.

Example 257

Carbonic acid3-benzyl-6-(4-fluoro-benzyl)-8-hydroxy-5,7-dioxo-3,5,6,7-tetrahydro-1,3,6-triaza-s-indacen-4-ylester ethyl ester 256 (140 mg, 0.28 mmol, 1 equiv.) was dissolved in 1,2dichloroethane (20 mL) and to this was added diphenyldiazomethane (72mg, 0.37 mmol, 1.3 equiv.) and heated at 70° C. under a nitrogenatmosphere for 24 hours. The reaction was then concentrated in vacuo andpurified by silica gel chromatography using 7/3 Hexanes/Ethyl acetate toobtain carbonic acid8-benzhydryloxy-3-benzyl-6-(4-fluoro-benzyl)-5,7-dioxo-3,5,6,7-tetrahydro-1,3,6-triaza-s-indacen-4-ylester ethyl ester 257 (78%, 135 mg, 0.22 mmol). ¹H NMR (300 MHz) CDCl₃ δ8.17 (s, 1 H), 7.91 (s, 1 H), 7.68 (d, J=7.2 Hz, 4 H), 7.21-7.42 (m, 12H), 6.95-7.06 (s, 4 H), 5.49 (s, 2 H), 4.76 (s, 2 H), 4.11 (q, J=6.9 Hz,2 H), 1.17 (t, J=6.9 Hz, 3 H). MS: 678.1 (M+23). TLC R_(f): 0.3Hexanes/Ethyl acetate (7/3)

Example 258

Carbonic acid8-benzhydryloxy-3-benzyl-6-(4-fluoro-benzyl)-5,7-dioxo-3,5,6,7-tetrahydro-1,3,6-triaza-s-indacen-4-ylester ethyl ester 257 (130 mg, 0.20 mmol) was dissolved in THF (5 mL,0.1 M) along with DMAP (24 mg, 0.40 mmol, 2 equiv.). A solution of K₂CO₃(276 mg, 1.99 mmol, 10 equiv.) was dissolved separately in H₂O) (6 mL)before transferring to the reaction mixture. The reaction was allowed tostir for 18 hr and quenched with HCl (20 mL, 1 N) and extracted withethyl acetate (2×30 ml). The organic layer was washed with saturatedNH₄Cl solution (25 mL), brine solution (25 mL) and dried over Na₂SO₄ andconcentrated in vacuo to yield4-Benzhydryloxy-1-benzyl-6-(4-fluoro-benzyl)-8-hydroxy-1H-1,3,6-triaza-s-indacene-5,7-dione258 (94%, 103 mg, 0.188 mmol) as an off white oil. ¹H NMR (300 MHz)CDCl₃ δ 8.28 (bs, 1 H), 7.94 (s, 1 H), 7.89 (s, 1 H), 7.64-7.43 (m, 4H), 7.17-7.43 (m, 12 H), 6.98-7.04 (s, 2 H), 5.57 (s, 2 H), 4.77 (s, 2H). MS: 584.1 (M+1).

Example 259

Benzhydryloxy-1-benzyl-6-(4-fluoro-benzyl)-8-hydroxy-1H-1,3,6-triaza-s-indacene-5,7-dione258 (103 mg, 0.177 mmol, 1 equiv.) was added to a flask containing DMF(4 mL) followed by K₂CO₃ (122 mg, 0.88 mmol, 5 equiv.). To this wasadded methyl iodide (MeI, 109 μL, 1.76 mmol, 10 equiv.) under a nitrogenatmosphere and stirred for 16 hours. To the reaction was added water (50mL) and extracted with ethyl acetate (2×40 mL). The organic layer waswashed several times with water (3×30 mL), saturated NaHCO₃ (40 mL),brine solution (30 mL). It was dried over Na₂SO₄, filtered andconcentrated in vacuo and purified by silica gel chromatography using7/3 Hexanes/Ethyl acetate to obtain4-benzhydryloxy-1-benzyl-6-(4-fluoro-benzyl)-8-methoxy-1H-1,3,6-triaza-s-indacene-5,7-dione259 (73%, 75 mg, 0.125 mmol). ¹H NMR (300 MHz) CDCl₃ δ 8.09 (s, 1 H),7.94 (s, 1 H), 7.88 (s, 1 H), 7.64-7.43 (m, 4 H), 7.41-7.46 (m, 2 H),7.17-7.43 (m, 10 H), 6.98-7.04 (m, 3 H), 5.56 (s, 2 H), 4.80 (s, 2 H),3.84 (s, 3 H). MS: 620.1 (M+23). TLC R_(f): 0.6 Hexanes/Ethyl acetate(1/1).

Example 260

4-Benzhydryloxy-1-benzyl-6-(4-fluoro-benzyl)-8-methoxy-1H-1,3,6-triaza-s-indacene-5,7-dione259 (54 mg, 0.092 mmol, 1 equiv.) was dissolved in CH₂Cl₂ (2 mL) andMeOH (0.5 mL) and under a nitrogen atmosphere. Sodium borohydride(NaBH₄, 736 μL, 0.37 mmol, 4 equiv., 0.5 M) was added. The reaction wasallowed to stir for 1 hour at room temperature and heated to 65° C. for2 hours before being quenched with water (5 mL) and extracted with ethylacetate (2×5 mL). The organic layer was washed several times with water(2×10 mL), brine solution (10 mL). It was dried over Na₂SO₄, filteredand concentrated in vacuo and purified by preparatory thin-layerchromatography (PTLC) using 3/2 Hexanes/Ethyl acetate to obtain 260(51%, 28 mg, 0.047 mmol).

¹H NMR (300 MHz) CDCl₃ δ 7.86 (d, J=7.2 Hz, 2 H), 7.59 (d, J=7.2 Hz, 2H), 7.46-7.32 (m, 4 H), 7.32-7.21 (m, 4 H), 7.03-7.18 (m, 6 H),6.91-7.01 (m, 2 H), 5.95 (bs, 1 H), 5.56 (s, 2 H), 5.62-5.52 (m, 1 H),5.28 (d, J=15.9 Hz, 1 H), 5.14 (d, J=15.9 Hz, 1 H), 4.49 (d, J=15.9 Hz,1 H), 3.37 (s, 3 H). MS: 622.0 (M+23). TLC R_(f): 0.25 Hexanes/Ethylacetate (3/2)

Example 261

4-Benzhydryloxy-1-benzyl-6-(4-fluoro-benzyl)-7-hydroxy-8-methoxy-6,7-dihydro-1H-1,3,6-triaza-s-indacen-5-one260 (28 mg, 0.047 mmol, 1 equiv.) was added to CH₂Cl₂ (1 mL) under anitrogen atmosphere. Triethylsilane (200 μL) was added, followed bytrifluoroacetic acid (200 μL). The reaction was allowed 1 hour andconcentrated in vacuo until thoroughly dried. Hexanes/Ethyl ether (15mL, 1/1 ratio) was added to the oil and sonicated. The resulting solidwas then filtered and washed in Hexanes and air dried to give7-(4-fluoro-benzyl)-5-hydroxy-9-methoxy-7,8-dihydro-pyrrolo[3,4-g]quinoxalin-6-one261 (100%, 20 mg, 0.047 mmol) as a light gray powder.

¹H NMR (300 MHz) CDCl₃ δ 9.11 (bs 1 H), 7.8S (s, 1 H), 7.33-7.23 (m, 5H), 7.01-7.07 (s, 4 H), 5.57 (s, 2 H), 4.71 (s, 2 H), 4.37 (s, 2 H),3.57 (s, 3 H). ¹⁹F NMR (300 MHz) CDCl₃ δ 62.25. MS: 418.2 (M+1)

Example 262

To 0.051 mmol crude 45 was added triethylamine (100 μL), DMAP (catalyticamount) and isopropylsulfonyl chloride (18 μl, 0.154 mmol). The reactionmixture was stirred at room temperature for 24 hours under an inertatmosphere. The reaction was monitored by TLC (EtOAc/hexane 3/7)(R_(f)44=0.5, R_(f) 45=0, R_(f) 262=0.2) and LC/MS. After completion ofthe reaction, the mixture was diluted with EtOAc (20 mL) and washed with1N HCl, saturated NaHCO₃ and brine. The organic phase was dried (MgSO₄),filtered and concentrated in vacuo. The residue was purified by silicagel chromatography (ethylacetate/hexane—3/7) to affordpropane-2-sulfonic acid9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-5-ylester 262 (8.7 mg, 29%).

Example 263

To a solution of 262 (8.7 mg, 0.015 mmol) dissolved in dichloromethane(1 mL) was added trifluoroacetic acid (100 μl) and triethylsilane (200μl). The reaction mixture was stirred at room temperature for 30 minunder an inert atmosphere then concentrated in vacuo. The residue wastriturated with diethyl ether/hexane (1/1) to afford thetrifluoroacetate salt of propane-2-sulfonic acid7-(4-fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-5-ylester 263 (5.3 mg, 0.010 mmol, 68%) as a yellow solid: ¹H NMR (CDCl₃) δ9.0 (d, 1H), 8.4 (d, 1H), 7.6 (m, 1H), 7.3 (m, 2H), 7.0 (t, 2H), 4.8 (s,2H), 4.6(s, 2H), 3.7 (m, 1H), 1.7 (m, 6H); MS: 431 (M+1).

Example 264

Triethylamine (100 μl), DMAP (catalytic amount) and p-tosyl-chloride (30mg, 0.154 mmol) were added to 0.051 mmol 45, The reaction mixture wasstirred at room temperature for 24 hours under an inert atmosphere. Thereaction was monitored by TLC (EtOAc/hexane 3/7) (R_(f) 44=0.5, R_(f)45=0, R_(f) 264=0.3) and LC/MS. After completion of the reaction, themixture was diluted with EtOAc (20 mL) and washed with 1N HCl, saturatedNaHCO₃ and brine. The organic phase was dried (MgSO₄), filtered andconcentrated in vacuo. The residue was purified by silica gelchromatography (ethylacetate/hexane—3/7) to afford toluene-4-sulfonicacid9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-5-ylester 264 (15.3 mg, 47%).

Example 265

To a solution of 264 (15.3 mg, 0.015 mmol) dissolved in dichloromethane(1 mL) was added trifluoroacetic acid (100 μl) and triethysilane (200μl). The reaction mixture was stirred at room temperature for ½ hoursunder an inert atmosphere then concentrated in vacuo. The residue wastriturated with diethyl ether/hexane (1/1) to afford thetrifluoroacetate salt of toluene-4-sulfonic acid7-(4-fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-5-ylester 265 (11.6 mg, 0.020 mmol, 83%) as a yellow solid: ¹H NMR (CDCl₃) δ8.9 (d, 1H), 8.0 (d, 1H), 7.8 (m, 1H), 7.3 (m, 6H), 7.0 (t, 2H), 5.3 (s,1H, OH), 4.7 (s, 2H), 4.4 (s, 2H), 2.4 (s, 3H); MS. 479 (M+1).

Example 266

Triethylamine (50 μl), DMAP (catalytic amount) and6-Morpholin-4-yl-pyridine-3-sulfonyl chloride (26.3 mg, 0.10 mmol) wereadded to 0.034 mmol 45. The reaction mixture was stirred at roomtemperature for 18 hours under an inert atmosphere. The reaction wasmonitored by TLC (EtOAc/hexane 3/7) (R_(f)44=0.5, R_(f) 45=0, R_(f)266=0.3) and LC/MS. After completion of the reaction, the mixture wasdiluted with EtOAc (20 mL) and washed with 1N HCl, saturated NaHCO₃ andbrine. The organic phase was dried (MgSO₄), filtered and concentrated invacuo. The residue was purified by silica gel chromatography(ethylacetate/hexane—3/7) to afford 6-morpholin-4-yl-pyridine-3-sulfonicacid9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-5-ylester 266 (14.6 mg, 59%).

Example 267

To a solution of 266 (14.6 mg, 0.020 mmol) dissolved in dichloromethane(1 mL) was added trifluoroacetic acid (100 μl) and triethylsilane (200μl). The reaction mixture was stirred at room temperature for ½ hoursunder an inert atmosphere then concentrated in vacuo. The residue wastriturated with diethyl ether/hexane (1/1) to afford the TFA salt of6-morpholin-4-yl-pyridine-3-sulfonic acid7-(4-fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-5-ylester 267 (9.0 mg, 68%) as a yellow solid: ¹H NMR (CDCl₃) δ 8.9 (d, 1H),8.6 (s, 1H), 8.0 (dd, 1H), 7.7 (dd, 1H), 7.5 (m, 1H), 7.3 (m, 2H), 7.0(t, 2H), 6.5 (d, 2H), 4.8 (s, 2H), 4.6 (s, 2H), 3.7 (d, 4H), 3.6 (d,4H); MS: 551 (M+1).

Example 268

Triethylamine (50 μl), DMAP (catalytic amount) and2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonyl chloride (27.4mg, 0.10 mmol) were added to 0.034 mmol 45. The reaction mixture wasstirred at room temperature for 18 hours under an inert atmosphere. Thereaction was monitored by TLC (EtOAc/hexane 3/7) (R_(f) 44=0.5, R_(f)45=0, R_(f) 268=0.4) and LC/MS. After completion of the reaction, themixture was diluted with EtOAc (20 mL) and washed with 1N HCl, saturatedNaHCO₃ and brine. The organic phase was dried (MgSO₄), filtered andconcentrated in vacuo. The residue was purified by silica gelchromatography (ethylacetate/hexane—3/7) to afford2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonic acid9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-5-ylester 268 (12.2 mg, 50%).

Example 269

To a solution of 268 (12.2 mg, 0.017 mmol) dissolved in dichloromethane(1 mL) was added trifluoroacetic acid (100 μl) and triethylsilane (200μl). The reaction mixture was stirred at room temperature for ½ hoursunder an inert atmosphere then concentrated in vacuo. The residue wastriturated with diethyl ether/hexane (1/1) to afford2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonic acid7-(4-fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-5-ylester 269, TFA salt, (9.0 mg, 76%) as a yellow solid: ¹H NMR (CDCl₃) δ9.0 (d, 1H), 8.5 (dd, 1H), 7.9 (m, 2H), 7.8 (m, 2H), 7.7 (m, 1H), 7.3(m, 2H), 7.0 (t, 2H), 4.8 (s, 2H), 4.6 (s, 2H), 4.4 (q, 2H), 3.9 (q,2H); MS: 562 (M+1).

Example 270

Triethylamine (50 μl), DMAP (catalytic amount) and1-methyl-1H-imidazole-4-sulfonyl chloride (18.1 mg, 0.10 mmol) wereadded to 0.034 mmol crude 45. The reaction mixture was stirred at roomtemperature for 18 hours under an inert atmosphere. The reaction wasmonitored by TLC (EtOAc/hexane 3/7) (R_(f) 44=0.5, R_(f) 45=0, R_(f)270=0.05) and LC/MS. After completion of the reaction, the mixture wasdiluted with EtOAc (20 mL) and washed with 1N HCl, saturated NaHCO₃ andbrine. The organic phase was dried (MgSO₄), filtered and concentrated invacuo to give the crude mixture of 1-methyl-1H-imidazole-4-sulfonic acid9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-5-ylester 270.

Example 271

To a solution of crude 270 dissolved in dichloromethane (1 mL) was addedtrifluoroacetic acid (100 μl) and triethylsilane (200 μl). The reactionmixture was stirred at room temperature for ½ hours under an inertatmosphere then concentrated in vacuo. The residue was purified by HPLCto afford 1-methyl-1H-imidazole-4-sulfonic acid7-(4-fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-5-ylester 271, TFA salt, (2.5 mg) as a yellow solid: ¹H NMR (CD₃OD) δ 8.9(d, 1H), 8.4 (d, 1H), 7.85 (s, 1H), 7.78 (s, 1H), 7.6 (m, 1H), 7.4 (m,2H), 7.1 (t, 2H), 4.8 (s, 2H), 4.5(s, 2H), 3.8 (s, 3H); MS: 469 (M+1).HPLC conditions: mobile phase A was 0.1% TFA in water, mobile phase bwas 0.1% TFA in CH₃CN; gradient from 5% to 60% B in 20 min; flow ratewas 20 mL/min; column was Phenomenex, luna 5μ, C18(2), 150 mm×21.1 mm.

Example 272

Triethylamine (50 μl), DMAP (catalytic amount) and2-acetylamino-4-methyl-thiazole-5-sulfonyl chloride (25.5 mg, 0.10 mmol)were added to 0.034 mmol 45. The reaction mixture was stirred at roomtemperature for 18 hours under an inert atmosphere. The reaction wasmonitored by TLC (EtOAc/hexane 3/7) (R_(f) 44=0.5, R_(f) 45=0,R_(f)272=0.2) and LC/MS. After completion of the reaction, the mixturewas diluted with EtOAc (20 mL) and washed with 1N HCl, saturated NaHCO₃and brine. The organic phase was dried (MgSO₄), filtered andconcentrated in vacuo. The residue was purified by silica gelchromatography (ethylacetate/hexane—3/7) to afford2-acetylamino-4-methyl-thiazole-5-sulfonic acid9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-5-ylester 272 (18.9 mg, 79%).

Example 273

To a solution of 272 (18.9 mg, 0.027 mmol) dissolved in dichloromethane(1 mL) was added trifluoroacetic acid (100 μl) and triethylsilane (200μl). The reaction mixture was stirred at room temperature for ½ hoursunder an inert atmosphere then concentrated in vacuo. The residue wastriturated with diethyl ether/hexane (1/1) to afford2-acetylamino-4-methyl-thiazole-5-sulfonic acid7-(4-fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-5-ylester 273, TFA salt, (13.2 mg, 74%) as a yellow solid: ¹H NMR (CD₃OD) δ8.9 (d, 1H), 8.2 (d, 1H), 7.6 (m, 1H), 7.4 (m, 2H), 7.1 (t, 2H), 4.7 (s,2H), 4,4 (s, 2H), 2.23 (s, 3H), 2.21 (s, 3H); MS: 543 (M+1).

Example 274

To a solution of trifluoro-methanesulfonic acid9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-5-yl ester 46 (28 mg, 0.045 mmol)dissolved in dichloromethane (2 mL) was added trifluoroacetic acid (100μl) and triethylsilane (200 μl). The reaction mixture was stirred atroom temperature for ½ hours under an inert atmosphere then concentratedin vacuo. The residue was triturated with diethyl ether/hexane (1/1) toafford trifluoro-methanesulfonic acid7-(4-fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-5-yl ester 274, (13.7 mg, 0.03 mmol,67%) as a yellow solid: ¹H NMR (CDCl₃) δ 9.0 (d, 1H), 8.4 (d, 1H), 7.7(dd, 1H), 7.3 (dd, 2H), 7.1 (t₇ 2H), 4.8 (s, 2H), 4.6 (s, 2H); MS: 457(M+1).

Example 275

To a solution of trifluoro-methanesulfonic acid9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-5-ylester 46 (40 mg, 0.064 mmol) dissolved in toluene (3 mL)/ethanol (0.6mL)/water (0.4 mL) was added K₂CO₃ (27 mg, 0.192 mmol),4-ethoxyphenolboronic acid (22 mg, 0.128 mmol) andtetrakis-(triphenylphosphine)-palladium(0) (15 mg, 0.013 mmol). Thereaction mixture in the flask was flashed with argon three tires. It wasthen heated to 120° C. under argon 3 hours. The reaction was monitoredby TLC (EtOAc/hexane 3/7) (R_(f)46=0.6, R_(f)275=0.4) and LC/MS. Aftercooling to room temperature, the mixture was diluted with EtOAc (20 mL)and washed with 1N HCl, saturated NaHCO₃ and brine. The organic phasewas dried (MgSO₄), filtered and concentrated in vacuo. The residue waspurified by silica gel chromatography (ethylacetate/hexane—1/3) toafford9-benzhydryloxy-5-(4-ethoxy-phenyl)-7-(4-fluoro-benzyl)-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one275 (8.0 mg, 21%) as a solid: ¹H NMR (CDCl₃) δ 9.0 (d, 1H), 8.1 (s, 1H),7.9 (d, 1H), 7.8-7.5 (dd, 4H), 7.5 (s, 1H), 7.4 (dd, 2H), 7.3-7.1 (m,10H), 7.0 (t, 2H), 4.8 (s, 2H), 4.1 (m, 2H), 4.0 (s, 1H), 1.4 (t, 3H);MS: 595 (M+1).

Example 276

To a solution of9-benzhydryloxy-5-(4-ethoxy-phenyl)-7-(4-fluoro-benzyl)-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one275 (8 mg, 0.013 mmol) dissolved in dichloromethane (1 mL) was addedtrifluoroacetic acid (100 μl) and triethylsilane (200 μl). The reactionmixture was stirred at room temperature for ½ hours under an inertatmosphere then concentrated in vacuo. The residue was triturated withdiethyl ether/hexane (1/1) to afford5-(4-ethoxy-phenyl)-7-(4-fluoro-benzyl)-9-hydroxy-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one276, TFA salt, (1.8 mg, 0.003 mmol, 25%) as a yellow solid: ¹H NMR(CDCl₃) δ 9.0 (d, 1H), 8.1 (d, 1H), 7.7 (m, 2H), 7.6 (dd, 1H), 7.5 (dd,2H), 7.2 (dd, 2H), 7.1 (t, 2H), 4.7 (s, 2H), 4.2(s, 2H), 4.1 (m, 2H),1.5 (t, 3H); MS: 429 (M+1).

Example 277

To a solution of trifluoro-methanesulfonic acid9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-5-ylester 46 (43 mg, 0.07 mmol) dissolved in toluene (3 mL)/ethanol (0.6mL)/water (0.4 mL) was added K₂CO₃ (29 mg, 0.21 mmol),(3-ethoxycarbonylphenyl)boronic acid (28 mg, 0.14 mmol) andtetrakis-(triphenylphosphine)-palladium(0) (16 mg, 0.014 mmol). Thereaction mixture in the flask was flashed with argon three times. It wasthen heated to 120° C. under argon 3 hours. The reaction was monitoredby TLC (EtOAc/hexane 3/7) (R_(f) 46=0.6, R_(f)277=0.3) and LC/MS. Aftercooling to room temperature, the mixture was diluted with EtOAc (20 mL)and washed with 1N HCl, saturated NaHCO₃ and brine. The organic phasewas dried (MgSO₄), filtered and concentrated in vacuo to afford crude3-[9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-5-yl]-benzoicacid ethyl ester 277.

Example 278

To a solution of 277 dissolved in dichloromethane (2 mL) was addedtrifluoroacetic acid (200 μl) and triethylsilane (400 μl). The reactionmixture was stirred at room temperature for ½ hours under an inertatmosphere then concentrated in vacuo. The residue was redissolved inDMSO (1 mL) and purified by prep-HPLC to afford3-[7-(4-fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-5-yl] benzoic acid ethyl ester 278, TFA salt, (25 mg,0.003 mmol, 44% in two steps) as a yellow solid: ¹H NMR (CDCl₃) δ 9.0(d, 1H), 8.2 (d, 1H), 8.0 (s, 1H), 7.7 (m, 1H), 7.6 (dd, 1H), 7.5 (dd,2H), 7.0 (m, 2H), 7.1 (t, 2H), 4.7 (dd, 2H), 4.4(q, 2H), 4.3 (dd, 2H),1.4 (t, 3H); MS: 457 (M+1). HPLC conditions: mobile phase A was 0.1% TFAin water, mobile phase b was 0.1% TFA in CH₃CN; gradient from 5% to 60%B in 20 min; flow rate was 20 mL/min; column was Phenomenex, luna 5μ,C18 (2), 150 mm×21.1 mm.

Example 279

To a solution of trifluoro-methanesulfonic acid9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-5-ylester 46 (23.6 mg, 0.038 mmol) dissolved in toluene (3 mL)/ethanol (0.6mL)/water (0.4 mL) was added K₂CO₃ (16 mg, 0.11 mmol),3,5-dimethylisoxazole-4-boronic acid (11 mg, 0.076 mmol) andtetrakis-(triphenylphosphine)-palladium(0) (9 mg, 0.007 mmol). Thereaction mixture in the flask was flashed with argon three times. It wasthen heated to 120° C. under argon 3 hours. The reaction was monitoredby LC/MS. After cooling to room temperature, the mixture was dilutedwith EtOAc (201 mL) and washed with 1N HCl, saturated NaHCO₃ and brine.The organic phase was dried (MgSO₄), filtered and concentrated in vacuoto afford crude9-benzhydryloxy-5-(3,5-dimethyl-isoxazol-4-yl)-7-(4-fluoro-benzyl)-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one279.

Example 280

To a solution of 279 dissolved in dichloromethane (1 mL) was addedtrifluoroacetic acid (100 μl) and triethylsilane (200 μl). The reactionmixture was stirred at room temperature for ½ hours under an inertatmosphere then concentrated in vacuo. The residue was dissolved in DMSO(1 mL) and purified by prep-HPLC to remove Ph₃PO. The crude mixture wasdiluted with EtOAC and extracted with 1N HCl. The aqueous phasecontaining product 280 was re-purified by HPLC to afford5-(3,5-dimethyl-isoxazol-4-yl)-7-(4-fluoro-benzyl)-9-hydroxy-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one280, (0.4 mg) as a TFA salt solid: ¹H NMR (CD₃OD) δ 9.0 (d, 1H), 8.1 (d,1H), 8.0 (s, 1H), 7.7 (m, 1H), 7.4 (dd, 1H), 7.1 (t, 2H), 4.8 (s, 2H),4.2(s, 2H), 2.0 (s, s, 2×3H); MS: 404 (M+1). HPLC conditions: mobilephase A was 0.1% TFA in water, mobile phase b was 0.1% TFA in CH₃CN;gradient from 5% to 60% B in 20 min; flow rate was 20 mL/min; column wasPhenomenex, luna 5μ, C18 (2), 150 mm×21.1 mm.

Example 281

To a solution of trifluoro-methanesulfonic acid9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-5-ylester 46 (33.5 mg, 0.05 mmol) dissolved in toluene (3 mL)/ethanol (0.6mL)/water (0.4 mL) was added K₂CO₃ (22 mg, 0.15 mmol),(2-ethoxycarbonylphenyl)boronic acid (22 mg, 0.10 mmol) andtetrakis-(triphenylphosphine)-palladium(0) (12.5 mg, 0.01 mmol). Thereaction mixture in the flask was flashed with argon three times. It wasthen heated to 120° C. under argon 3 hours. The reaction was monitoredby TLC (EtOAc/hexane 3/7) (R_(f)46=0.6, R_(f) 281=0.5) and LC/MS. Aftercooling to room temperature, the mixture was diluted with EtOAc (20 mL)and washed with 1N HCl, saturated NaHCO₃ and brine. The organic phasewas dried (MgSO₄), filtered and concentrated in vacuo. The residue waspurified by flash chromatography on silica gel with EtOAc/Hexane (3/7)to afford pure2-[9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-5-yl]-benzoicacid ethyl ester 281, 9 mg, 26.8%.

Example 282

To a solution of 281 dissolved in dichloromethane (2 mL) was addedtrifluoroacetic acid (200 μl) and triethylsilane (400 μl). The reactionmixture was stirred at room temperature for ½ hours under an inertatmosphere then concentrated in vacuo. The residue was triturated withdiethyl ether/hexane (1/1) to afford2-[7-(4-fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-5-yl]-benzoicacid ethyl ester 282, TEA salt, (2.5 mg) as a yellow solid: ¹H NMR(CD₃OD) δ 8.9 (d, 1H), 8.0 (d, 1H), 8.0 (s, 1H), 7.8-7.6 (m, 3H), 7.5(dd, 1H), 7.3 (m, 2H+1H), 7.0 (t, 2H), 4.7 (dd, 2H), 4.1(dd, 2H), 3.7(m, 2H), 0.6 (t 3H); MS: 457 (M+1).

Example 283

To a solution of trifluoro-methanesulfonic acid9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-5-ylester 46 (40 mg, 0.064 mmol) dissolved in toluene (3 mL)/ethanol (0.6mL)/water (0.4 mL) was added K₂CO₃ (29 mg, 0.16 mmol),(2,6-difluorophenyl)boronic acid (20 mg, 0.128 mmol) andtetrakis-(triphenylphosphine)-palladium(0) (15 mg, 0.0 1mmol). Thereaction mixture in the flask was flashed with argon three times. It wasthen heated to 120° C. under argon for 3 hours. The reaction wasmonitored by TLC (EtOAc/hexane 3/7) (R_(f)46=0.6, R_(f) 283a=0.4, R_(f)283b=0.3) and LC/MS. After cooling to room temperature, the mixture wasdiluted with EtOAc (20 mL) and washed with 1N HCl, saturated NaHCO₃ andbrine. The organic phase was dried (MgSO₄), filtered and concentrated invacuo. The residue was purified by flash chromatography on silica gelwith EtOAc/Hexane (3/7) to separate pure9-benzhydryloxy-5-(2,6-difluoro-phenyl)-7-(4-fluoro-benzyl)-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one283a, 6 mg, 17%; and pure9-benzhydryloxy-7-(4-fluoro-benzyl)-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one283b, 11.0 mg, 36%.

Example 284

To a solution of 283a (9 mg) dissolved in dichloromethane (1 mL) wasadded trifluoroacetic acid (100 μl) and triethylsilane (200 μl). Thereaction mixture was stirred at room temperature for ½ hours under aninert atmosphere then concentrated in vacuo. The residue was trituratedwith diethyl ether/hexane (1/1) to afford5-(2,6-difluoro-phenyl)-7-(4-fluoro-benzyl)-9-hydroxy-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one284, TFA salt, (3.2 mg) as a yellow solid: ¹H NMR (CDCl,) δ 9.0 (d, 1H),8.0 (d, 1H), 7.6 (m, 1H), 7.5 (dd, 1H), 7.2 (m, 2H), 7.1 (m, 4H), 4.7(s, 2H), 4.2(s, 2H); MS: 421 (M+1).

Example 285

To a solution of 283b (11 mg) dissolved in dichloromethane (1 mL) wasadded trifluoroacetic acid (100 μl) and triethylsilane (200 μl). Thereaction mixture was stirred at room temperature for ½ hours under aninert atmosphere then concentrated in vacuo. The residue was trituratedwith diethyl ether/hexane (1/1) to afford7-(4-fluoro-benzyl)-9-hydroxy-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one285, TFA salt, (3.9 mg) as a yellow solid: ¹H NMR (CDCl₃) δ 9.1 (d, 1H),8.3 (d, 1H), 7.6 (m, 1H), 7.35 (s, 1H), 7.33 (m, 2H), 7.0 (t, 2H), 4.8(s, 2H), 4.4(s, 2H); MS: 309 (M+1).

Example 286

To a solution of trifluoro-methanesulfonic acid9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-5-ylester 46 (40 mg, 0.064 mmol) dissolved in toluene (3 mL)/ethanol (0.6mL)/water (0.4 mL) was added K₂CO₃ (29 mg, 0.16 mmol),2-fluoropyridine-3-boronic acid (18 mg, 0.128 mmol) andtetrakis-(triphenylphosphine)-palladium(0) (15 mg, 0.01 mmol). Thereaction mixture in the flask was flashed with argon three times. It wasthen heated to 120° C. under argon 3 hours. The reaction was monitoredby TLC (EtOAc/hexane 3/7) (R_(f) 46=0.6, R_(f) 286=0.1) and LC/MS. Aftercooling to room temperature, die mixture was diluted with EtOAc (20 mL)and washed with 1N HCl, saturated NaHCO₃ and brine. The organic phasewas dried (MgSO₄), filtered and concentrated in vacuo. The residue waspurified by flash chromatography on silica gel with EtOAc/Hexane (1/1)to afford pure9-benzhydryloxy-7-(4-fluoro-benzyl)-5-(2-fluoro-pyridin-3-yl)-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one(15), 10.6 mg, 29%.

Example 287

To a solution of 286 (10.6 mg) dissolved in dichloromethane (1 mL) wasadded trifluoroacetic acid (100 μl) and triethylsilane (200 μl). Thereaction mixture was stirred at room temperature for ½ hours under aninert atmosphere then concentrated in vacuo. The residue was purified byHPLC to afford7-(4-fluoro-benzyl)-5-(2-fluoro-pyridin-3-yl)-9-hydroxy-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one287, TFA salt, (3.2 mg) as a yellow solid: ¹H NMR (CDCl₃) δ 9.0 (d, 1H),8.4 (d, 1H), 7.9 (d, 1H), 7.8 (dd, 1H), 7.5 (m, 1H), 7.4 (m, 1H), 7.3(m, 2H), 7.0 (t, 2H), 4.7 (dd, 2H), 4.2(dd, 2H); MS: 404 (M+1). HPLCconditions: mobile phase A was 0.1% TFA in water, mobile phase b was0.1% TFA in CH₃CN; gradient from 5% to 60% B in 20 min; flow rate was 20mL/min; column was Phenomenex, luna 5μ, C18(2), 150 mm×21.1 mm.

Example 288

To a solution of trifluoro-methanesulfonic acid9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-5-ylester 46 (40 mg, 0.064 mmol) dissolved in toluene (3 mL)/ethanol (0.6mL)/water (0.4 mL) was added K₂CO₃ (29 mg, 0.16 mmol),2-methoxypyridine-3-boronic acid (20 mg, 0.128 mmol) andtetrakis-(triphenylphosphine)-palladium(0) (15 mg, 0.01 mmol). Thereaction mixture in the flask was flashed with argon three times. It wasthen heated to 120° C. under argon 3 hours. The reaction was monitoredby TLC (EtOAc/hexane 3/7) (R_(f) 46=0.6, R_(f) 288=0.1) and LC/MS. Aftercooling to room temperature, the mixture was diluted with EtOAc (20 mL)and washed with 1N HCl, saturated NaHCO₃ and brine. The organic phasewas dried (MgSO₄), filtered and concentrated in vacuo. The residue waspurified by flash chromatography on silica gel with EtOAc/Hexane (1/1)to afford pure9-benzhydryloxy-7-(4-fluoro-benzyl)-5-(2-methoxy-pyridin-3-yl)-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one(17), 18.0 mg, 48%.

Alternatively, according to a modified Suzuki coupling method of C. H.Chen; Tetrahedron Letter; EN; 44; 5747-5750; 2003, to a solution oftrifluoro-methanesulfonic acid9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-5-ylester 46 (266.2 mg, 0.428 mmol) dissolved in toluene (5 mL) was addedNa₂CO₃ (2M in water, 500 μl), 2-methoxypyridine-3-boronic acid (164 mg,1.07 mmol) and tetrakis-(triphenylphosphine)-palladium(0) (100 mg, 0.086mmol). The reaction mixture in the flask was flashed with argon threetimes. It was then heated to 120° C. under argon 4 hours. The reactionwas monitored by TLC (EtOAc/hexane 3/7) (R_(f)1=0.6, R_(f)17=0.1) andLC/MS. After cooling to room temperature, the mixture was diluted withEtOAc (20 mL) and washed with 1N HCl, saturated NaHCO₃ and brine. Theorganic phase was dried (MgSO₄), filtered and concentrated in vacuo. Theresidue was purified by flash chromatography on silica gel withEtOAc/Hexane (1/1) to afford pure9-benzhydryloxy-7-(4-fluoro-benzyl)-5-(2-methoxy-pyridin-3-yl)-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one288, 125 mg, 50%. ¹H NMR (CDCl₃) δ 9.0 (dd, 1H), 8.3 (dd, 1H), 8.2 (s,1H), 7.8 (dd, 4H), 7.7 (dd, 1H), 7.4 (dd, 1H), 7.3-7.1 (m, 8H), 7.0 (m,2H+1H), 4.7 (dd, 2H), 4.1(dd, 2H), 3.8 (s, 1H), MS: 582 (M+1).

Example 289

To a solution of 288 (18 mg) dissolved in dichloromethane (1 mL) wasadded trifluoroacetic acid (100 μl) and triethylsilane (200 μl). Thereaction mixture was stirred at room temperature for ½ hours under aninert atmosphere then concentrated in vacuo. The residue was purified byHPLC to afford7-(4-fluoro-benzyl)-5-(2-methoxy-pyridin-3-yl)-9-hydroxy-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one289, TFA salt, (11.6 mg, 68%) as a yellow solid: ¹H NMR (CDCl₃) δ 9.0(d, 1H), 8.3 (d, 1H), 7.9 (d, 1H), 7.5 (m, 2H), 7.2 (m, 1H+1H), 7.0 (m,2H+1H), 4.7 (dd, 2H), 4.1(dd, 2H), 3.8 (s, 1H); MS: 416 (M+1). HPLCconditions: mobile phase A was 0.1I% TFA in water, mobile phase b was0.1% TFA in CH₃CN; gradient from 5% to 60% B in 20 mm; flow rate was 20mL/min; column was Phenomenex, luna 5μ, C18(2), 150 mm×21.1 mm.

Example 290

To a solution of9-benzhydryloxy-7-(4-fluoro-benzyl)-5-(2-methoxy-pyridin-3-yl)-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one288 (99 mg, 0.17 mmol) dissolved in methanol (20 mL) was addedp-toluenesulfonic acid monohydrate (390 mg, 2.05 mmol) and lithiumiodide (1.37 g, 10.26 mmol). The reaction mixture was heated to 120° C.under nitrogen for 10 hours. The reaction was monitored by LC/MS. Aftercooling to room temperature, the solvent was removed under reducedpressure. The residue was dissolved in 2 mL DMSO and 100 μl of TFA. Itwas purified by HPLC to afford7-(4-fluoro-benzyl)-9-hydroxy-5-(2-hydroxy-pyridin-3-yl)-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one290, TFA salt, (44.4 mg, 51%) as a yellow solid: ¹H NMR (CD₃OD) δ 8.9(dd, 1H), 8.2(dd, 1H), 7.7 (m, 1H+1H), 7.6 (d, 2H), 7.4 (m, 2H), 7.1 (m,2H), 6.6 (t, 1H), 4.8 (dd, 2H), 4.3(d, 2H); HPLC conditions: mobilephase A was 0.1% TFA in water, mobile phase b was 0.1% TFA in CH₃CN;gradient from 5% to 60% B in 20 min; flow rate was 20 mL/min; column wasPhenomenex, luna 5μ, C18(2), 150 mm×21.1 mm.

Example 291

To a solution of the trifluoroacetate salt of(2-piperazin-1-yl-ethyl)-phosphonic acid dimethyl ester 187 (0.023 g,0.077 mmol) in 1 ml DMF was added diisopropylethylamine (33 μL, 0.192mmol). This mixture was added to a solution of9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-5-carboxylic acid 213 (0.020 g, 0.038 mmol) that hadbeen mixed with HATU (0.0293 g, 0.077 mmol) in 1 ml of DMF. The reactionwas stirred at rt under inert atmosphere for 3 h, at which time TLC in100% EtOAc showed complete consumption of starting material. Thereaction mixture was introduced directly onto silica gel (99/1EtOH/Et₃N) to give 20 mg of(2-{4-[9-benzhydryloxy-7-(4-fluoro-ben7.yl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-5-carbonyl]-piperazin-1-yl}-ethyl)-phosphonicacid dimethyl ester 291 after flash chromatography.

Example 292

An excess of trimethylsilyl bromide (TMSBr, 0.015 g, 0.1 mmol) was addedto(2-{4-[9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-5-carbonyl]-piperazin-1-yl}-ethyl)-phosphonic aciddimethyl ester 291 in 1 mL of CH₂Cl₂. After stirring at room temperature(rt) for 16 h, volatiles were removed under vacuum and the residue wastriturated with Et₂O to provide pure the HBr salt of(2-{4-[7-(4-Fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-5-carbonyl]-piperazin-1-yl}-ethyl)-phosphonic acid 292(12 mg, 95%) as a yellow solid. ¹H NMR (DMSO) δ: 8.95 (d, 1H), 8.75 (d,1H), 8.54 (1H, d), 8.35 (bm, 1H), 7.78 (m, 2H), 7.52 (m, 2H), 7.4-7.32(bm, 2H), 7.15 (t, 2H), 4.85 (bm, 1H) 4.45 (bm, 2H) 2.04 (bm, 2H); ³¹PNMR (DMSO) δ 19.9; MS: 529 (M+H).

Example 293

To a solution of2-[(2-{4-[9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-5-carbonyl]-piperazin-1-yl}-ethyl)-phenoxy-phosphinoyloxy]-propionicacid ethyl ester 223 (15 mg, 0.017 mmol) in 1 ml CH₂Cl₂ at rt was addedan excess of TFA (10 μL, 0.085 mmol) and triethylsilane (30 μL, 0.17mmol). The reaction was stirred under N₂ with monitoring via LC/MS.After 8 h, the volatiles were removed by vacuum and the residuedissolved in 1 mL of a 1/1 mixture of acetonitrile/water. 50 μL of 1MNaOH was added and the reaction was stirred at rt overnight. At thistime, the product was introduced directly onto reverse phase HPLC toafford, after lyophilization,2-[(2-{4-[7-(4-fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-5-carbonyl]-piperazin-1-yl}-ethyl)-hydroxy-phosphinoyloxy]-propionicacid as the trifluoroacetate salt, 293 (5 mg, 39%). ¹H NMR (D₂O) δ: 9.10(d, 1H), 8.95-8.72 (bm, 1H), 8.14 (bs, 1H), 7.20-7.3 (bm, 2H), 6.92-7.08(bs, 2H), 4.65-4.25 (m, 4H), 3.78-3.65 (bs, 1H), 3.62-3.10 (bm, 9H),2.75 (d, 2H), 1.95 (m, 2H), 1.35 (d, 3H); ³¹P NMR (D₂O) δ 19.5; MS: 629(M+H).

Example 294

To(2-{4-[9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-5-carbonyl]-piperazin-1-yl}-ethyl)-phosphonicacid dimethyl ester 291 (5 mg, 0.0069 mmol) in 1 mL CH₂Cl₂ is addedCF₃CO₂H (6 μL, 0.035 mmol) and triethylsilane (12 μL, 0.07 mmol). After2 h, the volatile reaction components were removed by vacuum and theresidue was washed with diethyl ether to give(2-{4-[7-(4-fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-5-carbonyl]-piperazin-1-yl}-ethyl)-phosphonicacid 294 as the trifluoroacetate salt (4.5 mg, 97%): ¹H NMR (CD₃OD) δ:8.90 (d, 0.7H) 8.74 (d, 0.3H), 8.45 (d, 0.3H), 8.31 (d, 0.7H), 7.75 (dd,0.7H), 7.55 (dd, 0.3H), 7.40 (m, 2H), 7.12 (m, 2H), 4.54 (s, 2H), 4.15(bs, 1H), 3.85 (s, 3H), 3.75 (s, 3H), 3.62-3.40 (bs, 2H), 3.12 (bs, 2H),2.45-2.30(m, 2H); ¹⁹F NMR (CD₃OD) δ ⁻78, ⁻127; ³¹P NMR (CD₃OD) δ 29; MS:556 (M+H).

Example 295

Imidazole (0.74 g, 10.8 mmol) and chlorotriisopropylsilane (TIPSCl, 1.15g, 6.0 mmol) were added to 5,8-dihydroxy-quinoline-6,7-dicarboxylic aciddimethyl ester (prepared by the method in Oguchi, S. Bulletin of theChemical Society of Japan 1974, 47, 1291, 1.5 g, 5.4 mmol) in 20 mL DMF.The reaction was stirred for 48 h at rt and then the reaction waspartitioned between 0.5 L methyl t-butyl ether and 150 mL saturated aq.LiCl. The organic layer was dried over Na₂SO₄ and the solvent removed byrotary evaporation. The residue (1.4 g, 3.2 mmol) was redissolved in 25mL DMF and treated with K₂CO₃ (0.66 g, 4.8 mmol) followed by methyliodide (MeI, 0.6 g, 4.8 mL) at rt. After 2 h, the reaction mixture wasconcentrated and purified by introduction of the reaction mixture ontosilica gel for flash chromatography (4/1 hexanes/ethyl acetate) to give5-methoxy-8-triisopropylsilanyloxy-quinoline-6,7-dicarboxylic aciddimethyl ester (1.4 g, 59% overall yield): ¹H NMR (CDCl₃) δ 8.85 (d,1H), 8.45 (d, 1H), 7.50 (dd, 1H), 4.05 (s, 3H), 3.95 (s, 3H), 3.90 (s,3H), 1.45 (septet, 3H), 1.05 (d, 9H); MS: 448 (M+H).

A 1M solution of TBAF in THF (4 ml) was added to5-methoxy-8-triisopropylsilanyloxy-quinoline-6,7-dicarboxylic aciddimethyl ester (0.85 g, 1.9 mmol) in 20 ml dry THF. The reaction wasstirred at rt for 1 h, at which time the reaction mixture wasconcentrated and the residue dissolved in 100 mL diethyl ether andwashed with 25 mL 1N HCl, followed by 25 mL of saturated aq. NaCl. Theorganic layer was concentrated and the residue was dissolved in 40 mLdichloroethane. Diphenyldiazomethane (0.7 g, 3.8 mmol) was added and thereaction temperature was raised to 70° C. for 24 h. The reaction mixturewas concentrated and the residue chromatographed on silica gel (1/1hexanes/EtOAc) to give8-benzhydryloxy-5-methoxy-quinoline-6,7-dicarboxylic acid dimethyl ester(0.8 g, 61% yield overall). ¹H NMR (CDCl₃) δ 8.85 (d, 1H), 8.45 (d, 1H),7.45 (dd, 1B), 3.98 (s, 3H), 3.85 (s, 3H), 3.74 (s, 3H); MS: 480 (M+Na).

Lithium hydroxide (LiOH, 0.07 g, 2.95 mmol) was added to8-benzhydryloxy-5-methoxy-quinoline-6,7-dicarboxylic acid dimethyl ester(0.27 g, 0.59 mmol) in 1 mL 3/1 THF/H₂O. The reaction was heated at 45°C. and after 24 h, the reaction was diluted with 50 mL dichloromethaneand acidified with 1 mL 0.1 M HCl. The organic layer was dried overNa₂SO₄ and concentrated to give 180 mg of an oil which was dissolved in5 mL THF, triethylamine (0.168 g, 1.2 mmol) and ethyl chloroformate(0.064 g, 0.6 mmol). After 2 h, the reaction was diluted with diethylether and washed with brine. The organic layer was dried over Na₂SO₄ andthe organic layer decanted from drying agent. The ether layer was cooledto 0° C. and a solution of ca. 0.3 M diazomethane in diethyl ether (4mL, ca. 1.2 mmol) was added dropwise. After stirring for 24 h to effectdiazotization, the ether layer was removed along with excessdiazomethane via rotary evaporation. The resulting residue was dissolvedin 4 mL of 1/1 THF/water, and silver(I) oxide (0.035 g, 0.15 mmol) wasadded. The reaction was heated to 60° C. for a period of 4 h, then thereaction mixture was diluted with 50 mL EtOAc and acidified with 10 ml1N HCl. The organic layer was dried over Na₂SO₄ and concentrated. Theresulting residue was then taken up in 2 mL THF, and treated withhydroxybenzotriazole (HOBt, 0.08 g, 0.6 mmol), dicyclohexylcarbodiimide(DCC, 0.12 g, 0.6 mmol) and 4-fluorobenzylamine (0.07 g, 0.6 mmol).After a period of 16 h, the reaction was introduced directly tochromatography on silica gel (100% diethyl ether) to give8-benzhydryloxy-6-[(4-fluoro-benzylcarbamoyl)-methyl]-5-methoxy-quinoline-7-carboxylicacid methyl ester (0.12 g, 38% overall yield): ¹H NMR (CDCl₃) δ 8.85 (d,1H), 8.35 (d, 1H), 7.60-6.8 (cm, 12H), 6.15 (s, 1H), 4.30 (m, 2H), 3.95(s, 3H), 3.75 (s, 3H), 3.65 (s, 2H), 3.54 (t, 1H); MS: 587 (M+Na).

A 60% sodium hydride (NaB) mineral oil dispersion (0.002 g, 0.06 mmolwas added to a solution of8-benzhydryloxy-6-[(4-fluoro-benzylcarbamoyl)-methyl]-5-methoxy-quinoline-7-carboxylicacid methyl ester (0.020 g, 0.04 mmol) in 1 mL of anhydrous DMF. Theresulting indigo-tinted solution was stirred at rt for a period of 30min, and then diluted with diethyl ether (50 ml) and washed with sat.aq. NH₄Cl (25 mL). The organic layer was dried over Na₂SO₄ and solventwas removed by rotary evaporation. The residue was purified by silicagel chromatography (1/1 hexanes/diethyl ether and then 100% MeOH toelute product fractions) to give9-benzhydryloxy-7-(4-fluoro-benzyl)-10-methoxy-5H-1,7-diaza-anthracene-6,8-dione295 (9 mg, 48%).

Example 296

9-Benzhydryloxy-7-(4-fluoro-benzyl)-10-methoxy-5H-1,7-diaza-anthracene-6,8-dione 295 (6 mg, 0.01 mmol) in 1 mL CH₂Cl₂was treated with 0.1 mL trifluoroacetic acid and 0.05 mL triethylsilane.After 1 h, volatiles were removed and the product was purified viatrituration with diethyl ether to give the trifluoroacetate salt of7-(4-Fluoro-benzyl)-9-hydroxy-10-methoxy-5H-1,7-diaza-anthracene-6,8-dione296 (5 mg, 62%): ¹H NMR (CDCl₃) δ 12.98 (s, 1H), 9.10 (d, 1H), 8.35 (d,1H), 7.65 (m, 1H), 7.55 (m, 2H), 7.04 (t, 2H), 5.2 (s, 2H), 4.75 (s,1H), 4.20 (s, 1H), 3.95 (s, 3H); MS: 367 (M+Na).

Example 297

Sodium borohydride (NaBH₄, 0.021 g, 0.56 mmol) was added to9-benzhydryloxy-7-(4-fluoro-benzyl)-10-methoxy-5H-1,7-diaza-anthracene-6,8-dione295 (30 mg, 0.056 mmol) in 1 mL EtOH at ⁻5° C. The reaction was stirredat low temperature for a period of 2 h, then the reaction was dilutedwith CH₂Cl₂ (25 mL) and washed with 10 mL sat. aq. sodium bicarbonatesolution. The aqueous layer was then washed twice with 25 ml portions ofCH₂Cl₂ and the combined organic layers washed with brine and dried overNa₂SO₄. The reduction product was purified on silica gel (100% Et₂O) togive 6 mg of9-benzhydryloxy-7-(4-fluoro-benzyl)-10-methoxy-5H-1,7-diaza-anthracene-6-hydroxy,8-one 297.

Example 298

9-Benzhydryloxy-7-(4-fluoro-benzyl)-10-methoxy-5H-1,7-diaza-anthracene-6-hydroxy,8-one 297 (6 mg, 0.01 mmol) was dissolved in 1 mL CH₂Cl₂ and treatedwith 0.1 mL trifluoroacetic acid and 0.1 mL triethylsilane. After 1 hr,volatiles were removed and the product was purified via trituration withdiethyl ether to give the trifluoroacetate salt of7-(4-Fluoro-benzyl)-9-hydroxy-10-methoxy-7H-1,7-diaza-anthracen-8-one298 (2 mg, 38%). ¹H NMR (CD₃OD) δ 9.35 (d, 1H), 8.75 (d, 1H), 7.80 (dd,1H), 7.33 (m, 2H), 7.08 (m, 3H), 6.85 (d, 1H), 5.15 (s, 2H), 3.95 (s,3H); MS: 351 (M+H).

Example 299

To 2,4-dimethoxybenzyl-alcohol (4.3 g, 25.6 mmol) andpyrrolidine-2,5-dione (succinimide, 1.2 g, 12.2 mmol) dissolved intetrahydrofuran (25 ml) and dichloromethane (25 ml) was addedtriphenyphosphine (6.4 g, 24.4 mmol). After cooling to 0° C.,diethylazidodicarboxylate (DEAD, 4.25 g, 24.4 mmol) was added dropwiseto the reaction mixture. The reaction mixture was then allowed to warmto room temperature and kept at room temperature with stirringovernight. Following concentration in vacuo, 100 ml of a(1:1)hexane/ether solution was added and this mixture was stored at 0°C. overnight. The resulting solid precipitate was filtered off and thefiltrate was concentrated in vacuo. The resulting residue was purifiedby silica gel chromatography (3/1—ethyl acetate/hexane) to afford1-(2,4-dimethoxy-benzyl)-pyrrolidine-2,5-dione 299 (1.4 g, 5.6 mmol,46%). ¹H NMR (CDCl₃) δ 7.07 (d, 1H), 6.38 (m, 2H), 4.60 (s, 2H), 3.76(s, 3H), 2.62 (s, 4H).

Example 300

To 1-(2,4-dimethoxy-benzyl)-pyrrolidine-2,5-dione 299 (1.4 g, 5.6 mmol)and pyridine-2,3-dicarboxylic acid dimethyl ester (1.13 g, 5.8 mmol)dissolved in tetrahydrofuran (60 ml) and methanol (7.0 ml) was added a60% dispersion of sodium hydride in mineral oil (NaH, 492 mg, 12.3mmol). The reaction mixture was warmed to 80° C. and kept at 80° C. withstirring overnight. The reaction mixture was placed in an ice bath andtitrated to a pH of 4 with 1 M HCl. 200 ml of ether was added and theresulting yellow solid was collected by filtration. The solid was washedtwice with ether, twice with water, and dried under high vacuum withheating to provide7-(2,4-dimethoxy-benzyl)-5,9-dihydroxy-pyrrolo[3,4-g]quinoline-6,8-dione300 (1.1 g, 52%). ¹H NMR (d-DMSO) δ 10.8 (broad, 2H), 9.0 (d, 1H), 8.67(d, 1H), 7.72 (m, 1H), 6.90 (d, 1H), 6.5 (d, 1H), 6.38 (dd, 1H), 4.58(s, 2H), 3.76 (s, 3H), 3.66 (s, 3H). MS: 382.1 (M+1)

Example 301

7-(2,4-Dimethoxy-benzyl)-5,9-dihydroxy-pyrrolo[3,4-g]quinoline-6,8-dione 300 (1.1 g, 2.9 mmol) was dissolved indioxane (14.5 ml) and H₂O (9.7 ml) and cooled to 0° C. To this reactionmixture was added 1.0 M NaOH (5.8 ml, 5.8 mmol), followed byethylchloroformate (347.3 mg, 3.2 mmol). After stirring at 0° C. for 30minutes, dioxane (10 ml) and ethylchloroformate (51 mg, 0.5 mmol) wereadded and the reaction stirred for another 30 minutes at 0° C. Thereaction mixture was quenched with the addition of acetic acid (0.6 ml)and concentrated in vacuo. The crude mixture was diluted with ethylacetate and washed once with 5% citric Acid (aqueous), twice with water,once with brine, and dried over magnesium sulfate. The resulting residuewas dissolved in 1,2-dichloroethane (30 ml) anddiphenyl-methanediazonium 38 (diphenyldiazomethane, 1.1 g, 5.6 mmol) wasadded. The reaction mixture was then stirred overnight at roomtemperature. Following dilution with dichloromethane, the reactionmixture was washed with once with water, once with brine, dried overmagnesium sulfate, and concentrated in vacuo. The residue was purifiedby silica gel chromatography (1/1—Hexanes/Ethyl Acetate) to affordcarbonic acid9-benzhydryloxy-7-(2,4-dimethoxy-benzyl)-6,8-dioxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-5-ylester ethyl ester 301 (1.2 g, 1.9 mmol, 66%). ¹H NMR (CDCl₃) δ 9.10 (dd,1H), 8.40 (dd, 1H), 7.95 (s, 1H), 7.68 (m, 1H), 7.60 (d, 4H), 7.15 (m,6H), 7.0 (d, 1H), 6.40 (d, 1H), 6.36 (d, 1H), 4.80 (s, 2H), 4.35 (q,2H), 3.75 (s, 3H), 3.73 (s, 3H), 1.31 (t, 3H). MS: 641.2 (M+23).

Example 302

Potassium carbonate (2.6 g, 19.0 mmol) and N,N-dimethyl-aminopyridine(DMAP, 0.464 g, 3.8 mmol) were added to carbonic acid9-benzhydryloxy-7-(2,4-dimethoxy-benzyl)-6,8-dioxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-5-ylester ethyl ester 301 (1.2 g, 1.9 mmol) dissolved in tetrahydrofuran (40ml) and water (20 ml) was added. After stirring overnight at roomtemperature, the reaction mixture was concentrated in vacuo and dilutedwith ethyl acetate. It was washed twice with 5% citric Acid (aqueous),twice with water, once with brine, dried over magnesium sulfate, andconcentrated in vacuo. The resulting residue was dissolved indimethylformamide (10 ml). To this reaction mixture was added potassiumcarbonate (1.24 g, 9.0 mmol) and iodomethane (methyl iodide, MeI, 2.55g, 18.0 mmol). After stirring overnight at room temperature, thereaction mixture was diluted with ethyl acetate, washed twice with 5%citric acid, twice with water, once with brine, and concentrated invacuo to afford9-benzhydryloxy-7-(2,4-dimethoxy-benzyl)-5-methoxy-pyrrolo[3,4-g]quinoline-6,8-dione302 (1.1 g, 1.9 mmol, 100%). ¹H NMR (d-DMSO) δ 9.16 (dd, 1H), 8.60 (dd,1H), 7.82 (s, 1H), 7.75 (m, 1H), 7.54 (d, 4H), 7.16 (m, 6H), 6.82(d,1H), 6.56 (d, 1H), 6.44 (dd, 1H), 4.66 (s, 2H), 4.10 (s, 3H), 3.76(s, 3H), 3.70 (s, 3H). MS: 583.2 (M+23).

Example 303

9-Benzhydryloxy-7-(2,4-dimethoxy-benzyl)-5-methoxy-pyrrolo[3,4-g]quinoline-6,8-dione302 (500 mg, 0.89 mmol) was dissolved in tetrahydrofuran (6.0 ml), water(1.2 ml), and isopropanol (2.4 ml) and cooled to 0° C. Lithiumborohydride (LiBH₄, 96.9 mg, 4.45 mol) was then added and the reactionmixture was removed from the ice bath and stirred at room temperaturefor 2 hours. After quenching with acetic acid (0.5 ml), the reactionmixture was diluted with ethyl acetate, washed with twice with water,once with brine, and concentrated in vacuo. The resulting residue wasdissolved in dichloromethane (9.2 ml) and triethylsilane (1.8 ml)₃, andcooled to 0° C. After adding trifluoroacetic acid (3.6 ml), the reactionmixture was warmed to room temperature and stirred at room temperaturefor 1 hour. The mixture was concentrated in vacuo and the resultingresidue was redissolved in trifluoroacetic acid (10 ml) andtriethylsilane (2 ml). It was then warmed to 75° C. and stirred at 75°C. for 2 hours. The reaction mixture was concentrated in vacuo andazeotroped three times with a (1:1) toluene/tetrahydrofuran solution.The resulting residue was triturated three times with a (3:1)hexane/ether mixture. The remaining solid in the filter funnel andreaction flask was dissolved in methanol, combined, and concentrated invacuo to afford9-hydroxy-5-methoxy-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one 303(240 mg,113%) ¹HNMR (d-DMSO) δ 8.84(dd, 1H), 8.58 (broad, 1H),8.50 (dd, 1H),7.60 (m, 1H), 4.60 (s, 2H), 3.94 (s, 3H). MS: 231.1 (M+1).

Example 304

Potassium carbonate (60.1 mg, 0.435 mmol), 4-methoxybenzylchloride (41mg, 0.26 mmol), and sodium iodide (6.3 mg, 0.043 mmol) were added to9-hydroxy-5-methoxy-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one 303 (20 mg,0.087 mmol) dissolved in dimethylformamide 8 (0.4 ml). The reactionmixture was warmed to 60° C. and stirred at 60° C. for one hour. Aftercooling the reaction mixture to 0° C., acetic acid (0.06 ml) was addedand the mixture was concentrated in vacuo. The residue was diluted withethyl acetate and washed once with 5% Citric Acid, twice with water,once with brine, and concentrated in vacuo. The residue was purified bysilica gel chromatography (9/1—dichloromethane/methanol) to afford5-methoxy-9-(4-methoxy-benzyloxy)-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one304 (16 mg, 0.046 mmol, 53%). ¹H NMR (CDCl₃) δ 9.0 (dd, 1H), 8.64 (dd,1H), 7.51 (d, 2H), 7.46 (m, 1H), 6.80 (d, 2H), 6.50 (broad, 1H), 5.60(s, 2H), 3.98 (s, 3N), 3.72 (s, 3H). MS: 351.1 (M+1).

Example 305

5-Methoxy-9-(4-methoxy-benzyloxy)-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one304 (25.4 mg, 0.073 mmol,) was dissolved in dimethylformamide (0.4 ml)and cooled to 0° C. Sodium hydride (3.6 mg, 0.095 mmol) was added,followed by stirring at 0° C. for 5 minutes.4-trifluoromethyl-benzylbromide (21.0 mg, 0.088 mmol) was added and thereaction mixture was allowed to warm to room temperature and kept atroom temperature with stirring for 5 minutes. It was cooled to 0° C.,quenched with acetic acid (0.030 ml), and concentrated in vacuo. Themixture was diluted with ethyl acetate, washed twice with water. oncewith brine, dried over magnesium sulfate, and concentrate in vacuo. Theresidue was purified by silica gel chromatography (99/1—ethylacetate/acetic acid) to afford5-Methoxy-9-(4-methoxy-benzyloxy)-7-(4-trifluoromethyl-benzyl)-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one305 (13 mg, 0.026 mmol, 35%). ¹H NMR δ 9.15 (dd, 1H), 8.60 (dd, 1H),7.60 (m, 4H), 7.40 (d, 2H), 6.80 (d, 2H), 5.85 (s, 2H), 4.80 (s, 2H),4.42 (s, 2H), 3.98 (s, 3H), 3.86 (s, 3H). MS: 509.2 (M+1).

Example 306

To5-methoxy-9-(4-methoxy-benzyloxy)-7-(4-trifluoromethyl-benzyl)-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one305 (13 mg, 0.026 mmol) dissolved in dicloromethane (0.200 ml) was addedtriethylsilane (TES, 0.05 ml) and trifluoroacetic acid (TFA, 0.100 ml),After stirring at room temperature for 15 minutes, the reaction mixturewas concentrated in vacuo and azeotroped three times with a (1:1)tetrahydrofuran to toluene mixture. The resulting residue was thentriturated three times with a (3:1) hexane to ether mixture to afford9-hydroxy-5-methoxy-7-(4-trifluoromethyl-benzyl)-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one306 (7 mg, 0.014 mmol, 54%). ¹H NMR (CD₃OD) δ 9.0 (dd, 1H), 8.58 (dd,1H), 7.60 (d, 2H), 7.40 (d, 2H), 4.80 (s, 2H), 4.50 (s, 2H), 3.95 (s,3H). ¹⁹F NMR δ−63, −76.2. MS: 389.1 (M+1).

Example 307

5-Methoxy-9-(4-methoxy-benzyloxy)-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one304 (17 mg, 0.049 mmol) was dissolved in dimethylformamide (0.3 ml) andcooled to 0° C. After adding sodium hydride (2.5 mg, 0.064 mmol), thereaction was stirred for 5 minutes at 0° C. 3,5-Dichlorobenzylchloride(11.5 mg, 0.059 mmol) and a catalytic amount of sodium iodide were thenadded. The reaction mixture was warmed to room temperature and stirredat room temperature for 30 minutes. It was then cooled to 0° C.,acidified with acetic acid (0.030 ml), and concentrated in vacuo. Theresulting residue was diluted with ethyl acetate, washed twice withwater, once with brine, and concentrated in vacuo. The residue waspurified by silica gel chromatography (99/1—ethyl acetate/acetic acid)to afford7-(3,5-dichloro-benzyl)-5-methoxy-9-(4-methoxy-benzyloxy)-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one307 (7 mg, 40%). ¹H NMR (CDCl₃) δ 9.0 (dd, 1H), 8.40 (dd, 1H), 7.60 (d,2H), 7.55 (m, 1H), 7.20 (m, 3H), 6.80 (d, 2H), 5.60 (s, 2H), 4.75(s,2H), 4.40 (s, 2H), 3.95 (s, 3H), 3.75 (s, 3H). MS: 509.1 (M+1).

Example 308

In a manner similar to the protocol described in Example 306,7-(3,5-dichloro-benzyl)-5-methoxy-9-(4-methoxy-benzyloxy)-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one307 (17 mg, 0.049 mmol) was deprotected to provide7-(3,5-dichloro-benzyl)-9-hydroxy-5-methoxy-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one308 (10 mg, 0.020 mmol, 41%). ¹H NMR (CD₃OD) δ 9.0 (dd, 1H), 8.60 (d,1H), 7.60 (m, 1H), 7.20 (m, 3H) 4.75 (s, 2H), 4.45 (s, 2H), 4.0 (s, 3H).¹⁹F δ−76. MS: 390.1 (M+1).

Example 309

To a solution of 1-(2-bromo-ethyl)-4-fluoro-benzene (587 mg, 3.7 mmol)and pyrroldine-2,5-dione (succinimide, 733.3 mg, 7.4 mmol) indimethylformamide (15 ml) was added potassium carbonate (2.0 g, 14.8mmol) and sodium iodide (277 mg, 1.9 mmol). The reaction mixture waswarmed to 60° C. and kept at 60° C. overnight with stirring. Thereaction mixture was cooled to room temperature and concentrated invacuo. The concentrate was diluted with ethyl acetate and washed twicewith a saturated sodium bicarbonate aqueous solution, twice with water,once with brine, and concentrated in vacuo. The residue was purified bysilica gel chromatography (100% ethylacetate) to afford1-[2-(4-fluoro-phenyl)-ethyl]-pyrrolidine-2,5-dione 309 (570 mg, 2.6mmol, 70%) as a solid. ¹H NMR (CDCl₃) δ 7.14 (m, 2H), 6.94 (t, 2H), 3.68(t, 2H), 2.84 (t, 2H), 2.63 (s, 4H).

Example 310

To 1-[2-(4-Fluoro-phenyl)-ethyl]-pyrrolidine-2,5-dione 309 (270 mg, 1.22mmol and pyridine-2,3-dicarboxylic acid dimethyl ester (261.6 mg, 1.34mmol) dissolved in tetrahydrofuran (12.0 ml) and methanol (1.4 ml) wasadded a 60% dispersion of sodium hydride in mineral oil (108 mg, 2.7mmol). The reaction mixture was warmed to 80° C. and kept at 80° C. withstirring overnight. The reaction mixture was then placed in an ice bathand titrated to a pH of 4 with 1 M HCl. Two hundred (200) ml ofdiethylether was then added and the resulting yellow solid was collectedby filtration. The solid was washed twice with ether, twice with water,and dried under high vacuum with heating to provide7-[2-(4-fluoro-phenyl)-ethyl]-5,9-dihydroxy-pyrrolo[3,4-g]quinoline-6,8-dione310 (250 mg, 0.71 mmol, 58%). ¹H NMR (d-DMSO) δ 10.7 (broad, 1H), 8.98(dd, 1H), 8.66 (dd, 1H), 7.73 (m, 1H), 7.18 (m, 2H), 7.04 (t, 2H), 3.72(t, 2H), 2.86 (t, 2H). MS: 353.1 (M+1).

Example 311

7-[2-(4-Fluoro-phenyl)-ethyl]-5,9-dihydroxy-pyrrolo[3,4-g]quinoline-6,8-dione310 (250 mg, 0.71 mmol) was dissolved in dioxane (3.6 ml) and H₂O (2.4ml) and cooled to 0° C. After 1.0 M NaOH (1.42 ml, 1.42 mmol) andethylchloroformate (84.6 mg, 0.78 mmol) were added, the reaction wasstirred at 0° C. for one hour. The reaction mixture was quenched withthe addition of acetic acid (0.6 ml) and concentrated in vacuo. Thecrude mixture was diluted with ethyl acetate and washed once with 5%Citric Acid (aqueous), twice with water, once with brine, dried overmagnesium sulfate, and concentrated in vacuo. The resulting residue wasdissolved in 1,2-dichloroethane (4.0 ml) and to this was addeddiphenyl-methanediazonium 38 (252 mg, 1.3 mmol). The reaction mixturewas then stirred overnight at room temperature. Following dilution withdichloromethane, the reaction mixture was washed with once with water,once with brine, dried over magnesium sulfate, and concentrated invacuo. The residue was then purified by silica gel chromatography(1/1—hexane/ethyl acetate) to afford carbonic acid9-benzhydryloxy-7-[2-(4-fluoro-phenyl)-ethyl]-6,8-dioxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-5-ylester ethyl ester 311 (251 mg, 0.425 mmol,65%). ¹H NMR (d-DMSO) δ 9.19(dd, 1H), 8.52 (dd, 1H), 7.90 (s, 1H), 7.80 (m, 1H), 7.54 (m, 4H), 7.20(m, 8H), 7.02 (t, 2H), 4.24 (q, 2H), 3.79 (t, 2H), 2.90 (t, 2H), 1.25(t, 3H). MS: 599.2 (M+23).

Example 312

To carbonic acid9-benzhydryloxy-7-[2-(4-fluoro-phenyl)-ethyl]-6,8-dioxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-5-ylester ethyl ester 311 (140 mg, 0.24 mmol) dissolved in tetrahydrofuran(0.50 ml) and water (0.25 ml) was added potassium carbonate (345.4 mg,2.5 mmol) and N,N-dimethyl-aminopyridine (DMAP, 29.3 mg, 3.8 mmol).After stirring overnight at room temperature, the reaction mixture wasconcentrated in vacuo and diluted with ethyl acetate. It was then washedtwice with 5% citric Acid (aqueous), twice with water, once with brine,dried over magnesium sulfate, and concentrated in vacuo. The resultingresidue was dissolved in dimethylformamide (3.0 ml). To this solutionwas added potassium carbonate (179 mg, 1.3 mmol) and iodomethane (319mg, 2.6 mmol). After stirring overnight at room temperature, thereaction mixture was diluted with ethyl acetate. It was then washedtwice with 5% citric Acid, twice with water, once with brine, andconcentrated in vacuo to afford9-benzhydryloxy-7-[2-(4-fluoro-phenyl)-ethyl]-5-methoxy-pyrrolo[3,4-g]quinoline-6,8-dione312 (130 mg, 0.24 mmol, 100%). ¹H NMR (CDCl₃) δ 9.16 (dd, 1H), 8.58 (dd,1H), 7.82 (s, 1H), 7.74 (m, 1H), 7.55 (m, 4H), 7.20 (m, 8H), 7.0 (t,2H), 4.04 (s, 3H), 3.87 (t, 2H), 2.91 (t, 2H). MS: 555.2 (M+23).

Example 313

9-Benzhydryloxy-7-(2,4-dimethoxybenzyl)-5-methoxy-pyrrolo[3,4-g]quinoline-6,8-dione312 (130 mg, 0.24 mmol) was dissolved in tetrahydrofuran (1.6 ml), water(0.64 ml), and isopropanol (0.32 ml) and cooled to 0° C. Lithiumborohydride (26.6 mg, 1.22 mmol) was then added and the reaction mixturewas removed from the ice bath and stirred at room temperature for 2hours. After quenching with acetic acid (0.12 ml), the reaction mixturewas diluted with ethyl acetate. It was then washed with twice withwater, once with brine, and concentrated in vacuo. The resulting residuewas dissolved in dichloromethane (1.2 ml) and triethylsilane (0.6 ml)and trifluoroacetic acid (3.6 ml). The reaction mixture was then stirredat room temperature for 1 hour. The mixture was then concentrated invacuo and azeotroped three times with a (1:1) toluene/tetrahydrofuransolution. The resulting residue was triturated three times with a (3:1)hexane/ether mixture and the remaining solid in the filter funnel andreaction flask was dissolved in methanol, combined, and concentrated invacuo to afford7-[2-(4-Fluoro-phenyl)-ethyl]-9-hydroxy-5-methoxy-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one313 (40 mg, 0.086 mmol, 36%). ¹H NMR (d-DMSO) δ 8.85 (dd, 1H), 8.648(dd, 1H), 7.65 (m, 1H), 7.28 (t, 2H), 7.06 (t, 2H), 4.60 (s, 2H), 3.95(s, 3H), 3.68 (t, 2H), 2.95 (t, 2H). ¹⁹F NMR δ 60.0-75.6. MS: 353.1(M+1).

Example 314

To(2-{[9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-5-carbonyl]-amino}-ethyl)-phosphonicacid diethyl ester 214 (16 mg, 0.023 mmol) dissolved in dichloromethane(0.30 ml) was added trimethylsilylbromide (TMS-Br, 39 mg, 0.25 mmol).After 4 hours of stirring at room temperature, moretrimethylsilylbromide (24 mg, 0.16 mmol) was added and the reactionmixture stirred for another 2 hours. The reaction mixture was cooled to0° C., quenched with methanol (1.0 ml), and concentrated in vacuo. Itwas then triturated three times (3/1—hexane/ether) and the remainingresidue in the flask and filter was dissolved in methanol, combined, andconcentrated in vacuo. The residue was dissolved in dimethysulfoxide(0.40 ml), filtered through a glass plug, and purified by reverse-phasepreparatory HPLC to provide(2-{[7-(4-fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-5-carbonyl]-amino}-ethyl)-phosphonicacid 314 (7 mg, 0.012 mmol, 52%). ¹H NMR (CD₃OD) δ 8.96 (d, 1H), 8.77(d, 1H), 7.78 (m, 1H), 7.42 (m, 2H), 7.10 (t, 2H), 4.80 (s, 2H), 4.63(s, 2H), 3.72 (m, 2H), 2.16 (m, 2H). ³¹P δ 25.0. ¹⁹F δ −78.0-116.0. MS:460.1 (M+1).

Example 315

To2-[(2-{[7-(4-fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-5-carbonyl]-amino}-ethyl)-phenoxy-phosphinoyloxy]-propionicacid ethyl ester 221 (15 mg, 0.024 mmol) dissolved in acetonitrile (0.10ml) and water (0.05 ml) was added 1.0 M NaOH (0.072 ml). The reactionmixture was stirred at room temperature for 3 hours, cooled to 0° C.,and quenched with 1.0 M HCl (0.1 ml). The mixture was concentrated invacuo and the resulting residue was redissolved in dimethylsulfoxide,filtered through a glass plug, and purified by reverse phase preparatoryHPLC to afford2-[(2-{[7-(4-fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-5-carbonyl]-amino}-ethyl)-hydroxy-phosphinoyloxy]-propionicacid 315 (9 mg, 0.014 mmol, 60%). ¹H NMR (CD₃OD) δ 9.0 (d, 1H), 8.80 (d,1H), 7.80 (m, 1H), 7.42 (M, 2H), 7.10 (t, 2H), 4.80 (d, 2H), 4.62 (s,2H), 3.75 (m, 2H), 2.20 (m, 2H), 1.46 (d, 3H). ³¹P δ 27.8. ¹⁹F δ −78.0,−118.0. MS: 532.1 (M+1).

Example 316

To a solution of9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-5-carboxylicacid methyl ester 212 (3 mg, 0056 mmol) in dichloromethane (1 mL) wereadded TFA (0.1 mL) and triethylsilane (0.2 mL). Stirring was continuedat the room temperature for 1 hour and the volatiles were evaporated invacuo. The residue was triturated in Et₂O/hexane to afford7-(4-fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-5-carboxylicacid methyl ester 316 (2.0 mg, 100%) as a yellow solid: ¹H NMR (CDCl₃) δ9.5 (d, 1H), 9.0 (m, 1H), 7.66 (dd, 1H), 7.35 (dd, 2H), 7.0 (t, 2H), 4.8(s, 2H), 4.7 (s, 2H), 4.0 (s, 3H); MS: 365 (M−1).

Example 317

To a solution of9-benzlhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-5-carboxylicacid 213 (6 mg, 0.0116 mmol) in DMF (0.5 mL) at the room temperaturewere added triethylamine (TEA, 5 μL, 0.034 mmol), cyclohexylamine (2.3μL, 0.022 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (EDCI, 4.4 mg, 0.022 mmol) and 1-hydroxybenzotriazole(HOBt, 2.3 mg, 0.0174 mmol). The solution was stirred under a nitrogenatmosphere for 5 hours and diluted with EtOAc. The organic layer waswashed with water, 1N aqueous HCl, saturated aqueous NaHCO₃ and brine,dried over MgSO₄ and concentrated in vacuo. The crude product waschromatographed on a silica gel column eluting with EtOAc/hexane toafford the protected final product, which was treated in dichloromethane(1 mL) with TFA (0.1 mL) and triethylsilane (0.2 mL) at the roomtemperature for 1 hour. The volatiles were evaporated in vacuo and theresidue was triturated in Et₂O/hexane to afford7-(4-fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-5-carboxylic acid cyclopentylamide 317 (2.6 mg, 54%) asyellow solid. ¹H NMR (CDCl₃) δ 8.96 (dd, 1H), 8.53 (d, 1H), 7.62 (dd,1H), 7.27 (m, 2H), 7.04 (t, 2H), 6.34 (m, 1H), 4.63 (s, 2H), 4.48 (m,3H), 2.2 (m, 2H), 1.50-1.90 (m, 6H); MS: 418 (M−1).

Example 318

9-Benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-5-carboxylic acid 213 (0.02 g,0.0386 mmol) was dissolved in 0.3 mL of dimethylformamide. To this wasadded 2-methylaminopyridine (0.0079 mL, 0.0772 mmol),diisopropylethylamine (0.027 mL, 0.1544 mmol),O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (0.03 g, 0.0772 mmol) and stirred at roomtemperature. After 15 hours, starting material was consumed. Purified byreverse phase HPLC (0.1% TFA, H₂O/ACN) to give7-(4-fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-5-carboxylicacid methyl-pyridin-2-yl-amide 318 (0.0017 g, 0.003 mmol, 8%.) ¹H NMR(CDCl₃) δ 9.02 (dd, 11H), 8.50 (d, 1H), 8.18 (d, 1H), 7.65 (dd, 1H),7.38 (m, 5H), 7.08 (dd, 2H), 4.94 (dd, J=15 Hz, 11Hz, 2H), 4.49 (d, J=17Hz, 1H), 4.19 (d, J=17Hz, 1H), 3.61 (s, 3H.) MS: 443 (M+1).

Example 319

9-Benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-5-carboxylic acid 213 (0.02 g, 0.0386 mmol) wasdissolved in 0.3 mL of dimethylformamide. To this was added2-aminothiazole (0.0077 mL, 0.0772 mmol), diisopropylethylamine (0.027mL, 0.1544 mmol),O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (0.03 g, 0.0772 mmol) and stirred at roomtemperature. After 15 hours, starting material was consumed. Purified byreverse phase HPLC (0.1% TFA, H₂O/ACN) to give7-(4-fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-5-carboxylicacid thiazol-2-ylamide 319 (0.01 g, 0.023 mmol, 60%.) ¹H NMR (CDCl₃) δ9.02 (dd, 1H), 8.61 (d, 1H), 7.65 (dd, 1H), 7.55 (d, 1H), 7.38 (dd, 2H),7.21 (d, 1H), 7.07 (dd, 2H), 4.78 (s, 2H), 4.67 (s, 2H.) MS: 435 (M+1).

Example 320

9-Benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-5-carboxylicacid 213 (0.02 g, 0.0386 mmol) was dissolved in 0.3 mL ofdimethylformamide. To this was added 2-amino-1,3,4-thiadiazole (0.0078mL, 0.0772 mmol), diisopropylethylamine (0.027 mL, 0.1544 mmol),O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (0.03 g, 0.0772 mmol) and stirred at roomtemperature. After 15 hours, starting material was consumed. Purified byreverse phase HPLC (0.1% TFA, H₂O/ACN) to give7-(4-fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-5-carboxylicacid [1,3,4]thiadiazole-2-ylamide 320 (0.0066 g, 0.015 mmol, 40%.) ¹HNMR (CDCl₃) δ 9.02 (dd, 1H), 8.81 (s, 1H), 8.65 (d, 1H), 7.65 (dd, 1H),7.38 (dd, 2H), 7.05 (dd, 2H), 4.74 (s, 2H), 4.64 (s, 2H.) MS: 436 (M+1).

Example 321

9-Benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-5-carboxylicacid 213 (0.02 g, 0.0386 mmol) was dissolved in 0.3 mL ofdimethylformamide. To this was added dimethylamine (2M in THF) (0.0386mL, 0.0772 mmol), diisopropylethylamine (0.027 mL, 0.1544 mmol),O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (0.03 g, 0.0772 mmol) and stirred at roomtemperature. After 15 hours, starting material was consumed. Purified byreverse phase HPLC (0.1% TFA, H₂O/ACN) to give7-(4-fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-5-carboxylicacid dimethylamide 321 (0.014 g, 0.037 mmol, 97%.) ¹H NMR (CDCl₃) δ 9.07(dd, 1H), 8.18 (d, 1H), 7.65 (dd, 31H), 7.03(dd, 2H), 4.79 (dd, 2H),4.53 (d, J=17Hz, 1H), 4.25 (d, J=17Hz, 1H), 3.24 (s, 3H), 3.21 (s, 3H.)MS: 380 (M+1).

Example 322

9-Benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-5-carboxylicacid 213 (0.02 g, 0.0386 mmol) was dissolved in 0.3 mL ofdimethylformamide. To this was added diethylamine (0.0056 mL, 0.0772mmol), diisopropylethylamine (0.027 mL, 0.1544 mmol),O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (0.03 g, 0.0772 mmol) and stirred at roomtemperature. After 15 hours, starting material was consumed. Purified byreverse phase HPLC (0.1% TFA, H₂O/ACN) to give7-(4-fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dilhydro-6H-pyrrolo[3,4-g]quinoline-5-carboxylicacid diethylamide 322 (0.0134 g, 0.033 mmol, 86%.) ¹H NMR (CDCl₃) δ 9.07(dd, 1H), 8.18 (d, 1H), 7.65 (m, 3H), 7.07(dd, 2H), 4.72 (dd, 2H), 4.56(d, J=1 7Hz, 1H), 4.23 (d, J=17 Hz, 1H), 3.66 (q, 2H), 3.11 (q, 2H),1.35 (t, 3H), 0.965 (t, 3H.) MS: 408 (M+1).

Example 323 HIV Integrase Assay (IC₅₀ Determination)

IC50 is the inhibitory concentration that reduces the strand transferactivity of recombinant integrase by 50%.

HIV Integrase assay was carried out in Reacti-Bind High Binding CapacityStreptavidin coated plates (Pierce # 15502) in 100 μl reactionsfollowing the method of Hazuda et al Nucleic Acids Res. (1994)22:1121-22. The wells of the plate are rinsed once with PBS. Each wellis then coated at room temperature for 1 h with 100 μl of 0.14 μMdouble-stranded donor DNA of Hazuda et al.

After coating, the plate was washed twice with PBS. 3′processing of thedonor DNA is started by adding 80 μl of Integrase/buffer mixture (25 mMHEPES, pH 7.3, 12.5 mM DTT, 93.75 mM NaCl, 12.5 mM MgCl₂, 1.25%Glycerol, 0.3125 μM integrase) to each well. 3′-Processing was allowedto proceed for 30 min at 37° C., after which, 10 μl of test compound and10 μl of 2.5 μM digoxigenin (DIG)-labeled, double-stranded Target DNA,according to Hazuda etal, were added to each well to allow strandtransfer to proceed for 30 min at 37° C. The plate was then washed threetimes with 2×SSC for 5 min and rinsed once with PBS. For detection ofintegrated product, 100 μl of a 1/2000 dilution of HRP-conjugatedanti-DIG antibody (Pierce #31468) were added to each well and incubatedfor 1 hour. The plate was then washed three times for 5 min each, with0.05% Tween-20 in PBS. For signal development and amplification, 100 μlof SuperSignal ELISA Femto Substrate (Pierce #37075) were added to eachwell, Chemiluminescence (in relative light units) was read immediatelyat 425 nm in the SPECTRAmax GEMINI Microplate Spectrophotometer usingthe end point mode at 5 sec per well. For IC₅₀ determinations, eightconcentrations of test compounds in a 1/2.2 dilution series were used.Certain compounds of the invention, including those in Tables 1-5, had astrand transfer IC₅₀ less than about 10 μM.

Example 324 Anti-HIV Assay (EC₅₀ Determination)

EC50 (also commonly referred to as ED50 or IC50) is the effectiveconcentration that inhibits 50% of viral production, 50% of viralinfectivity, or 50% of the virus-induced cytopathic effect.

Anti-HIV assay was carried out in 96-well Clear Bottom Black Assay Plate(Costar # 3603) in 100 μl of culture medium, using the CellTiter-Glo™Reagent (Promega # G7570) for signal detection. MT-2 cells (1.54×10⁴cells) were infected with wild-type virus at an m.o.i. of about 0.025,and grown in the presence of various drug concentrations (serial 5-folddilutions) in 100 μl of RPMI medium containing 10% FBS, 2% glutamine, 1%HEPES and 1% penicillin/streptomycin for 5 days. At the end of theincubation period, 100 μl of CellTiter-Glo™ Reagent was added to eachwell in the Assay Plate and the chemiluminescence (in relative lightunits) was measured after 10 mins of incubation with the Wallac Victor²1420 MultiLabel Counter. Certain compounds of the invention, includingthose in Tables 1-5, had an anti-HIV MT2 EC₅₀ less than about 10 μM.

Example 325 Cytotoxicity Assay (CC₅₀ Determination)

For the determination of compound cytotoxicity, the plate and reagentsare the same as those of anti-HIV assay. Uninfected MT-2 cells (1.54×10⁴cells)were grown in the presence of various drug concentrations (serial3-fold dilutions) in 100 μl of RPMI medium containing 10% FBS, 2%glutamine, 1% HEPES and 1% penicillin/streptomycin for 5 days. At theend of the incubation period, 100 μl of CellTiter-Glo™ Reagent was addedto each well in the assay plate and the chemiluminescence (in relativelight units) was measured after 10 mins of incubation with the WallacVictor² 1420 MultiLabel Counter. Certain compounds of the invention,including those in Tables 1-5, had cytotoxicity MT2 CC₅₀ less than about10 μM.

The foregoing specification teaches the principles of the presentinvention, with Examples provided for the purpose of illustration, andfully discloses how to make and use the present invention. The inventionis not limited to the particular embodiments described herein butincludes all modifications within the scope of the appended claims andtheir equivalents. Those skilled in the art will recognize throughroutine experimentation that various changes and modifications can bemade without departing from the scope of this invention.

All publications, including, but not limited to, patents and patentapplications cited in this specification, are herein incorporated byreference as if each individual publication were specifically and fullyset forth.

1. A pharmaceutical composition comprising a pharmaceutically acceptablecarrier and a therapeutically effective amount of a compound having thestructure:

wherein: A¹ is independently selected from C(R²)₂, CR²OR, CR²OC(═O)R,C(═O), C(═S), CR²SR, and C(═NR), A² is independently selected fromC(R²)₂—C(R³)₂, C(R²)═C(R³) and C(═O)C(R³)₂; Q is CR⁴;

L is selected from a bond, O, S, S—S, S(═O), S(═O)₂, S(═O)₂NR, NR, N—OR,C₁-C₁₂ alkylene, C₁-C₁₂ substituted alkylene, C₂-C₁₂ alkenylene, C₂-C₁₂substituted alkenylene, C₂-C₁₂ alkynylene, C₂-C₁₂ substitutedalkynylene, C(═O)NH, OC(═O)NH, NHC(═O)NH, C(═O), C(═O)NH(CH₂)_(n), or(CH₂CH₂O)_(n), where n is optionally 1, 2, 3, 4, 5, or 6; X is selectedfrom O, S, NH, NR, N—OR, N—NR₂, N—CR₂OR and N—CR₂NR₂; Ar is selectedfrom (a) a C₃-C₁₂ carbocycle, C₃-C₁₂ substituted carbocycle, C₆-C₂₀aryl, C₆-C₂₀ substituted aryl, C₂-C₂₀ heteroaryl, and C₂-C₂₀ substitutedheteroaryl; or (b) a saturated, unsaturated or aromatic ring or ringsystem having a mono- or bicyclic carbocycle or heterocycle containing 3to 12 ring atoms; R², R³ and R⁴ are each independently selected from H,F, Cl, Br, I, OH, —NH₂, —NH₃ ⁺, —NHR, —NR₂, —NR₃ ⁺, C₁-C₈ alkylhalide,carboxylate, sulfate, sulfamate, sulfonate, 5-7 membered ring sultam,C₁-C₈ alkylsulfonate, C₁-C₈ alkylamino, 4-dialkylaminopyridinium, C₁-C₈alkylhydroxyl, C₁-C₈ alkylthiol, —SO₂R, —SO₂Ar, —SOAr, —SAr, —SO₂NR₂,—SOR, —CO₂R, —C(═O)NR₂, 5-7 membered ring lactam, 5-7 membered ringlactone, —CN, —N₃, —NO₂, C₁-C₈ alkoxy, C₁-C₈ trifluoroalkyl, C₁-C₈alkyl, C₁-C₈ substituted alkyl, C₃-C₁₂ carbocycle, C₃-C₁₂ substitutedcarbocycle, C₆-C₂₀ aryl, C₆-C₂₀ substituted aryl, C₂-C₂₀ heteroaryl, andC₂-C₂₀ substituted heteroaryl, polyethyleneoxy, phosphonate, phosphate,and a prodrug moiety; when taken together on a single carbon, two R² ortwo R³ may form a spiro ring; R¹ is independently selected from CR₃,NRSO₂R, OC(═O)NR₂ OC(═O)R, SR, H, F, Cl, Br, I, OH, —NH₂, —NH₃ ⁺, —NHR,—NR₂, —NR₃ ⁺, C₁-C₈ alkylhalide, carboxylate, sulfate, sulfamate,sulfonate, 5-7 membered ring sultam, C₁-C₈ alkylsulfonate, C₁-C₈alkylamino, 4-dialkylaminopyridinium, C₁-C₈ alkylhydroxyl, C₁-C₈alkylthiol, —SO₂R, —SO₂Ar, —SOAr, —SAr, —SO₂NR₂, —SOR, —CO₂R, —C(═O)NR₂,5-7 membered ring lactam, 5-7 membered ring lactone, —CN, —N₃, —NO₂,C₁-C₈ alkoxy, C₁-C₈ trifluoroalkyl, C₁-C₈ alkyl, C₁-C₈ substitutedalkyl, C₃-C₁₂ carbocycle, C₃-C₁₂ substituted carbocycle, C₆-C₂₀ aryl,C₆-C₂₀ substituted aryl, C₂-C₂₀ heteroaryl, and C₂-C₂₀ substitutedheteroaryl, polyethyleneoxy, phosphonate, phosphate, and a prodrugmoiety; R is independently selected from H, C₁-C₈ alkyl, C₁-C8substituted alkyl, C₆-C₂₀ aryl, C₆-C₂₀ substituted aryl, C₂-C₂₀heteroaryl, and C₂-C₂₀ substituted heteroaryl, polyethyleneoxy,phosphonate, phosphate, and a prodrug moiety; R^(X2) is independentlyselected from H, C₁-C₈ alkyl, C₁-C₈ substituted alkyl, C₆-C₂₀ aryl,C₆-C₂₀ substituted aryl, C₂-C₂₀ heteroaryl, and C₂-C₂₀ substitutedheteroaryl, polyethyleneoxy, phosphonate, phosphate, a prodrug moiety,and a protecting group; and the tautomers, salts, solvates, resolvedenantiomers and purified diastereomers thereof; with the proviso thatwhen Y═Z is C═C(OH), X is O, A¹ is C(═O), A² is C(R²)═C(R³), and Q isCH, then L is not a bond; and further comprising a therapeuticallyeffective amount of an AIDS treatment agent selected from an HIVinhibitor agent, an anti-infective agent, and an immunomodulator.
 2. Thepharmaceutical composition of claim 1 wherein the HIV inhibitor agent isan HIV-protease inhibitor.
 3. The pharmaceutical composition of claim 1wherein the HIV inhibitor agent is a nucleoside reverse transcriptaseinhibitor.
 4. The pharmaceutical composition of claim 3 wherein saidnucleoside reverse transcriptase inhibitor is 3′-azido-3′-deoxythymidine(zidovudine, AZT), 2′-deoxy-3′-thiacytidine (3TC),2′,3′-dideoxy-2′,3′-didehydroadenosine (D4A), 2′, 3′-dideoxy-2′,3′-didehydrothymidine (D4T), carbovir (carbocyclic2′,3′-dideoxy-2′,3′-didehydroguanosine), 2′,3′-dideoxycytidine (ddC),2′,3′-dideoxyadenosine (ddA), 2′,3′-dideoxyinosine (ddI), PMEA, or PMPA.5. The pharmaceutical composition of claim 1 wherein the HIV inhibitoragent is a non-nucleoside reverse transcriptase inhibitor.
 6. A processfor making a pharmaceutical composition comprising combining apharmaceutically acceptable carrier and a compound having the structure:

wherein: A¹ is independently selected from C(R²)₂, CR²OR, CR²OC(═O)R,C(═O), C(═S), CR²SR, and C(═NR), A² is independently selected fromC(R²)₂—C(R³)₂, C(R²)═C(R³) and C(═O)C(R³)₂; Q is CR⁴;

L is selected from a bond, O, S, S—S, S(═O), S(═O)₂, S(═O)₂NR, NR, N—OR,C₁-C₁₂ alkylene, C₁-C₁₂ substituted alkylene, C₂-C]₂ alkenylene, C₂-C₁₂substituted alkenylene, C₂-C₁₂ alkynylene, C₂-C₁₂ substitutedalkynylene, C(═O)NH, OC(═O)NH, NHC(═O)NH, C(═O), C(═O)NH(CH₂)_(n), or(CH₂CH₂0)_(n), where n is optionally 1,2, 3, 4, 5, or 6; X is selectedfrom O, S, NH, NR, N—OR, N—NR₂, N—CR₂OR and N—CR₂NR₂; Ar is selectedfrom (a) a C₃-C₁₂ carbocycle, C₃-C₁₂ substituted carbocycle, C₆-C₂₀aryl, C₆-C₂₀ substituted aryl, C₂-C₂₀ heteroaryl, and C₂-C₂₀ substitutedheteroaryl; or (b) a saturated, unsaturated or aromatic ring or ringsystem having a mono- or bicyclic carbocycle or heterocycle containing 3to 12 ring atoms; R², R³ and R⁴ are each independently selected from H,F, Cl, Br, I, OH, —NH₂, —NH₃ ⁺, —NHR, —NR₂, —NR₃ ⁺, C₁-C₈ alkylhalide,carboxylate, sulfate, sulfamate, sulfonate, 5-7 membered ring sultam,C₁-C₈ alkylsulfonate, C₁-C₈ alkylamino, 4-dialkylaminopyridinium, C₁-C₈alkylhydroxyl, C₁-C₈ alkylthiol, —SO₂R, —SO₂Ar, —SOAr, —SAr, —SO₂NR₂,—SOR, —CO₂R, —C(═O)NR₂, 5-7 membered ring lactam, 5-7 membered ringlactone, —CN, —N₃, —NO₂, C₁-C₈ alkoxy, C₁-C₈ trifluoroalkyl, C₁-C₈alkyl, C₁-C₈ substituted alkyl, C₃-C₁₂ carbocycle, C₃-C₁₂ substitutedcarbocycle, C₆-C₂₀ aryl, C₆-C₂₀ substituted aryl, C₂-C₂₀ heteroaryl, andC₂-C₂₀ substituted heteroaryl, polyethyleneoxy, phosphonate, phosphate,and a prodrug moiety; when taken together on a single carbon, two R² ortwo R³ may form a spiro ring; R¹ is independently selected from CR₃,NRSO₂R, OC(═O)NR₂ OC(═O)R, SR, H, F, Cl, Br, I, OH, —NH₂, —NH₃ ⁺, —NHR,—NR₂, —NR₃ ⁺, C₁-C₈ alkylhalide, carboxylate, sulfate, sulfamate,sulfonate, 5-7 membered ring sultam, C₁-C₈ alkylsulfonate, C₁-C₈alkylamino, 4-dialkylaminopyridinium, C₁-C₈ alkylhydroxyl, C₁-C₈alkylthiol, —SO₂R, —SO₂Ar, —SOAr, —SAr, —SO₂NR₂, —SOR, —CO₂R, —C(═O)NR₂,5-7 membered ring lactam, 5-7 membered ring lactone, —CN, —N₃, —NO₂,C₁-C₈ alkoxy, C₁-C₈ trifluoroalkyl, C₁-C₈ alkyl, C₁-C₈ substitutedalkyl, C₃-C₁₂ carbocycle, C₃-C₁₂ substituted carbocycle, C₆-C₂₀ aryl,C₆-C₂₀ substituted aryl, C₂-C₂₀ heteroaryl, and C₂-C₂₀ substitutedheteroaryl, polyethyleneoxy, phosphonate, phosphate, and a prodrugmoiety; R is independently selected from H, C₁-C₈ alkyl, C₁-C₈substituted alkyl, C₆-C₂₀ aryl, C₆-C₂₀ substituted aryl, C₂-C₂₀heteroaryl, and C₂-C₂₀ substituted heteroaryl, polyethyleneoxy,phosphonate, phosphate, and a prodrug moiety; R^(X2) is independentlyselected from H, C₁-C₈ alkyl, C₁-C₈ substituted alkyl, C₆-C₂₀ aryl,C₆-C₂₀ substituted aryl, C₂-C₂₀ heteroaryl, and C₂-C₂₀ substitutedheteroaryl, polyethyleneoxy, phosphonate, phosphate, a prodrug moiety,and a protecting group; and the tautomers, salts, solvates, resolvedenantiomers and purified diastereomers thereof; with the proviso thatwhen Y=Z is C═C(OH), X is O, A¹ is C(═O), A² is C(R²)═C(R³), and Q isCH, then L is not a bond.
 7. A method of inhibiting HIV integrase,comprising the administration to a mammal in need of such treatment of atherapeutically effective amount of a compound having the structure:

wherein: A¹ is independently selected from C(R²)₂, CR²OR, CR²OC(═O)R,C(═O), C(═S), CR²SR, and C(═NR), A² is independently selected fromC(R²)₂—C(R³)₂, C(R²)═C(R³) and C(═O)C(R³)₂; Q is CR⁴;

L is selected from a bond, O, S, S—S, S(—O), S(═O)₂, S(═O)₂NR, NR, N—OR,C₁-C₁₂ alkylene, C₁-C₁₂ substituted alkylene, C₂-C₁₂ alkenylene, C₂-C₁₂substituted alkenylene, C₂-C₁₂ alkynylene, C₂-C₁₂ substitutedalkynylene, C(═O)NH, OC(═O)NH, NHC(═O)NH, C(═O), C(═O)NH(CH₂)_(n), or(CH₂CH₂O)_(n), where n is optionally 1, 2, 3, 4, 5, or 6; X is selectedfrom O, S, NH, NR, N—OR, N—NR₂, N—CR₂OR and N—CR₂NR₂; Ar is selectedfrom (a) a C₃-C₁₂ carbocycle, C₃-C₁₂ substituted carbocycle, C₆-C₂₀aryl, C₆-C₂₀ substituted aryl, C₂-C₂₀ heteroaryl, and C₂-C₂₀ substitutedheteroaryl; or (b) a saturated, unsaturated or aromatic ring or ringsystem having a mono- or bicyclic carbocycle or heterocycle containing 3to 12 ring atoms; R², R³ and R⁴ are each independently selected from H,F, Cl, Br, I, OH, —NH₂, —NH₃ ⁺, —NHR, —NR₂, —NR₃ ⁺, C₁-C₈ alkylhalide,carboxylate, sulfate, sulfamate, sulfonate, 5-7 membered ring sultam,C₁-C₈ alkylsulfonate, C₁-C₈ alkylamino, 4-dialkylaminopyridinium, C₁-C₈alkylhydroxyl, C₁-C₈ alkylthiol, —SO₂R, —SO₂Ar, —SOAr, —SAr, —SO₂NR₂,—SOR, —CO₂R, —C(═O)NR₂, 5-7 membered ring lactam, 5-7 membered ringlactone, —CN, —N₃, —NO₂, C₁-C₈ alkoxy, C₁-C₈ trifluoroalkyl, C₁-C₈alkyl, C₁-C₈ substituted alkyl, C₃-C₁₂ carbocycle, C₃-C₁₂ substitutedcarbocycle, C₆-C₂₀ aryl, C₆-C₂₀ substituted aryl, C₂-C₂₀ heteroaryl, andC₂-C₂₀ substituted heteroaryl, polyethyleneoxy, phosphonate, phosphate,and a prodrug moiety; when taken together on a single carbon, two R² ortwo R³ may form a spiro ring; R¹ is independently selected from CR₃,NRSO₂R, OC(═O)NR₂ OC(═O)R, SR, H, F, Cl, Br, I, OH, —NH₂, —NH₃ ⁺, —NHR,—NR₂, —NR₃ ⁺, C₁-C₈ alkylhalide, carboxylate, sulfate, sulfamate,sulfonate, 5-7 membered ring sultam, C₁-C₈ alkylsulfonate, C₁-C₈alkylamino, 4-dialkylaminopyridinium, C₁-C₈ alkylhydroxyl, C₁-C₈alkylthiol, —SO₂R, —SO₂Ar, —SOAr, —SAr, —SO₂NR₂, —SOR, —CO₂R, —C(═O)NR₂,5-7 membered ring lactam, 5-7 membered ring lactone, —CN, —N₃, —NO₂,C₁-C₈ alkoxy, C₁-C₈ trifluoroalkyl, C₁-C₈ alkyl, C₁-C₈ substitutedalkyl, C₃-C₁₂ carbocycle, C₃-C₁₂ substituted carbocycle, C₆-C₂₀ aryl,C₆-C₂₀ substituted aryl, C₂-C₂₀ heteroaryl, and C₂-C₂₀ substitutedheteroaryl, polyethyleneoxy, phosphonate, phosphate, and a prodrugmoiety; R is independently selected from H, C₁-C₈ alkyl, C₁-C₈substituted alkyl, C₆-C₂₀ aryl, C₆-C₂₀ substituted aryl, C₂-C₂₀heteroaryl, and C₂-C₂₀ substituted heteroaryl, polyethyleneoxy,phosphonate, phosphate, and a prodrug moiety; R^(X2) is independentlyselected from H, C₁-C₈ alkyl, C₁-C₈ substituted alkyl, C₆-C₂₀ aryl,C₆-C₂₀ substituted aryl, C₂-C₂₀ heteroaryl, and C₂-C₂₀ substitutedheteroaryl, polyethyleneoxy, phosphonate, phosphate, a prodrug moiety,and a protecting group; and the tautomers, salts, solvates, resolvedenantiomers and purified diastereomers thereof, with the proviso thatwhen Y═Z is C═C(OH), X is O, A¹ is C(═O), A² is C(R²)═C(R³), and Q isCH, then L is not a bond.
 8. A method of treating infection by HIV, orof treating AIDS or ARC, comprising administration to a mammal in needof such treatment of a therapeutically effective amount of a compoundhaving the structure:

wherein: A¹ is independently selected from C(R²)₂, CR²OR, CR²OC(═O)R,C(═O), C(═S), CR²SR, and C(═NR), A² is independently selected fromC(R²)₂—C(R³)₂, C(R²)═C(R³) and C(═O)C(R³)₂; Q is CR⁴;

L is selected from a bond, O, S, S—S, S(═O), S(═O)₂, S(═O)₂NR, NR, N—OR,C₁-C₁₂ alkylene, C₁-C₁₂ substituted alkylene, C₂-C₁₂ alkenylene, C₂-C₁₂substituted alkenylene, C₂-C₁₂ alkynylene, C₂-C₁₂ substitutedalkynylene, C(═O)NH, OC(═O)NH, NHC(═O)NH, C(═O), C(═O)NH(CH₂)_(n), or(CH₂CH₂O)_(n), where n is optionally 1, 2, 3, 4, 5, or 6; X is selectedfrom O, S, NH, NR, N—OR, N—NR₂, N—CR₂OR and N—CR₂NR₂; Ar is selectedfrom (a) a C₃-C₁₂ carbocycle, C₃-C₁₂ substituted carbocycle, C₆-C₂₀aryl, C₆-C₂₀ substituted aryl, C₂-C₂₀ heteroaryl, and C₂-C₂₀ substitutedheteroaryl; or (b) a saturated, unsaturated or aromatic ring or ringsystem having a mono- or bicyclic carbocycle or heterocycle containing 3to 12 ring atoms; R², R³ and R⁴ are each independently selected from H,F, Cl, Br, I, OH, —NH₂, —NH₃ ⁺, —NHR, —NR₂, —NR₃ ⁺, C₁-C₈ alkylhalide,carboxylate, sulfate, sulfamate, sulfonate, 5-7 membered ring sultam,C₁-C₈ alkylsulfonate, C₁-C₈ alkylamino, 4-dialkylaminopyridinium, C₁-C₈alkylhydroxyl, C₁-C₈ alkylthiol, —SO₂R, —SO₂Ar, —SOAr, —SAr, —SO₂NR₂,—SOR, —CO₂R, —C(═O)NR₂, 5-7 membered ring lactam, 5-7 membered ringlactone, —CN, —N₃, —NO₂, C₁-C₈ alkoxy, C₁-C₈ trifluoroalkyl, C₁-C₈alkyl, C₁-C₈ substituted alkyl, C₃-C₁₂ carbocycle, C₃-C₁₂ substitutedcarbocycle, C₆-C₂₀ aryl, C₆-C₂₀ substituted aryl, C₂-C₂₀ heteroaryl, andC₂-C₂₀ substituted heteroaryl, polyethyleneoxy, phosphonate, phosphate,and a prodrug moiety; when taken together on a single carbon, two R² ortwo R³ may form a spiro ring; R¹ is independently selected from CR₃,NRSO₂R, OC(═O)NR₂ OC(═O)R, SR, H, F, Cl, Br, I, OH, —NH₂, —NH₃ ⁺, —NHR,—NR₂, —NR₃ ⁺, C₁-C₈ alkylhalide, carboxylate, sulfate, sulfamate,sulfonate, 5-7 membered ring sultam, C₁-C₈ alkylsulfonate, C₁-C₈alkylamino, 4-dialkylaminopyridinium, C₁-C₈ alkylhydroxyl, C₁-C₈alkylthiol, —SO₂R, —SO₂Ar, —SOAr, —SAr, —SO₂NR₂, —SOR, —CO₂R, —C(═O)NR₂,5-7 membered ring lactam, 5-7 membered ring lactone, —CN, —N₃, —NO₂,C₁-C₈ alkoxy, C₁-C₈ trifluoroalkyl, C₁-C₈ alkyl, C₁-C₈ substitutedalkyl, C₃-C₁₂ carbocycle, C₃-C₁₂ substituted carbocycle, C₆-C₂₀ aryl,C₆-C₂₀ substituted aryl, C₂-C₂₀ heteroaryl, and C₂-C₂₀ substitutedheteroaryl, polyethyleneoxy, phosphonate, phosphate, and a prodrugmoiety; R is independently selected from H, C₁-C₈ alkyl, C₁-C₈substituted alkyl, C₆-C₂₀ aryl, C₆-C₂₀ substituted aryl, C₂-C₂₀heteroaryl, and C₂-C₂₀ substituted heteroaryl, polyethyleneoxy,phosphonate, phosphate, and a prodrug moiety; R^(X2) is independentlyselected from H, C₁-C₈ alkyl, C₁-C₈ substituted alkyl, C₆-C₂₀ aryl,C₆-C₂₀ substituted aryl, C₂-C₂₀ heteroaryl, and C₂-C₂₀ substitutedheteroaryl, polyethyleneoxy, phosphonate, phosphate, a prodrug moiety,and a protecting group; and the tautomers, salts, solvates, resolvedenantiomers and purified diastereomers thereof; with the proviso thatwhen Y=Z is C═C(OH), X is O, Al is C(═O), A² is C(R²)═C(R³), and Q isCH, then L is not a bond.
 9. A method of treating a disorder affectingwhite blood cells, comprising: administering to a patient in need ofwhite-blood-cell targeting a phosphonate prodrug of a compound havingthe structure:

wherein: A¹ is independently selected from C(R²)₂, CR²OR, CR²OC(═O)R,C(═O), C(═S), CR²SR, and C(═NR), A² is independently selected fromC(R²)₂—C(R³)₂, C(R²)═C(R³) and C(═O)C(R³)₂; Q is CR⁴;

L is selected from a bond, O, S, S—S, S(═O), S(═O)₂, S(═O)₂NR, NR, N—OR,C₁-C₁₂ alkylene, C₁-C₁₂ substituted alkylene, C₂-C₁₂ alkenylene, C₂-C₁₂substituted alkenylene, C₂-C₁₂ alkynylene, C₂-C₁₂ substitutedalkynylene, C(═O)NH, OC(═O)NH, NHC(═O)NH, C(═O), C(═O)NH(CH₂), or(CH₂CH₂O)_(n), where n is optionally 1, 2, 3, 4, 5, or 6; X is selectedfrom O, S, NH, NR, N—OR, N—NR₂, N—CR₂OR and N—CR₂NR₂; Ar is selectedfrom (a) a C₃-C₁₂ carbocycle, C₃-C₁₂ substituted carbocycle, C₆-C₂₀aryl, C₆-C₂₀ substituted aryl, C₂-C₂₀ heteroaryl, and C₂-C₂₀ substitutedheteroaryl; or (b) a saturated, unsaturated or aromatic ring or ringsystem having a mono- or bicyclic carbocycle or heterocycle containing 3to 12 ring atoms; R², R³ and R⁴ are each independently selected from H,F, Cl, Br, I, OH, —NH₂, —NH₃ ⁺, —NHR, —NR₂, —NR₃ ⁺, C₁-C₈ alkylhalide,carboxylate, sulfate, sulfamate, sulfonate, 5-7 membered ring sultam,C₁-C₈ alkylsulfonate, C₁-C₈ alkylamino, 4-dialkylaminopyridinium, C₁-C₈alkylhydroxyl, C₁-C₈ alkylthiol, —SO₂R, —SO₂Ar, —SOAr, —SAr, —SO₂NR₂,—SOR, —CO₂R, —C(═O)NR₂, 5-7 membered ring lactam, 5-7 membered ringlactone, —CN, —N₃, —NO₂, C₁-C₈ alkoxy, C₁-C₈ trifluoroalkyl, C₁-C₈alkyl, C₁-C₈ substituted alkyl, C₃-C₁₂ carbocycle, C₃-C₁₂ substitutedcarbocycle, C₆-C₂₀ aryl, C₆-C₂₀ substituted aryl, C₂-C₂₀ heteroaryl, andC₂-C₂₀ substituted heteroaryl, polyethyleneoxy, phosphonate, phosphate,and a prodrug moiety; when taken together on a single carbon, two R² ortwo R³ may form a spiro ring; R¹ is independently selected from CR₃,NRSO₂R, OC(═O)NR₂ OC(═O)R, SR, H, F, Cl, Br, I, OH, —NH₂, —NH₃ ⁺, —NHR,—NR₂, —NR₃ ⁺, C₁-C₈ alkylhalide, carboxylate, sulfate, sulfamate,sulfonate, 5-7 membered ring sultam, C₁-C₈ alkylsulfonate, C₁-C₈alkylamino, 4-dialkylaminopyridinium, C₁-C₈ alkylhydroxyl, C₁-C₈alkylthiol, —SO₂R, —SO₂Ar, —SOAr, —SAr, —SO₂NR₂, —SOR, —CO₂R, —C(═O)NR₂,5-7 membered ring lactam, 5-7 membered ring lactone, —CN, —N₃, —NO₂,C₁-C₈ alkoxy, C₁-C₈ trifluoroalkyl, C₁-C₈ alkyl, C₁-C₈ substitutedalkyl, C₃-C₁₂ carbocycle, C₃-C₁₂ substituted carbocycle, C₆-C₂₀ aryl,C₆-C₂₀ substituted aryl, C₂-C₂₀ heteroaryl, and C₂-C₂₀ substitutedheteroaryl, polyethyleneoxy, phosphonate, phosphate, and a prodrugmoiety; R is independently selected from H, C₁-C₈ alkyl, C₁-C₈substituted alkyl, C₆-C₂₀ aryl, C₆-C₂₀ substituted aryl, C₂-C₂₀heteroaryl, and C₂-C₂₀ substituted heteroaryl, polyethyleneoxy,phosphonate, phosphate, and a prodrug moiety; R^(X2) is independentlyselected from H, C₁-C₈ alkyl, C₁-C₈ substituted alkyl, C₆-C₂₀ aryl,C₆-C₂₀ substituted aryl, C₂-C₂₀ heteroaryl, and C₂-C₂₀ substitutedheteroaryl, polyethyleneoxy, phosphonate, phosphate, a prodrug moiety,and a protecting group; and the tautomers, salts, solvates, resolvedenantiomers and purified diastereomers thereof; with the proviso thatwhen Y=Z is C═C(OH), X is O, A¹ is C(═O), A² is C(R²)═C(R³), and Q isCH, then L is not a bond.
 10. A method of targeting a compound to whiteblood cells, comprising: (a) selecting a compound having a firststructure:

wherein: A¹ is independently selected from C(R²)₂, CR²OR, CR²OC(═O)R,C(═O), C(═S), CR²SR, and C(═NR), A² is independently selected fromC(R²)₂—C(R³)₂, C(R²)═C(R³) and C(═O)C(R³)₂; Q is CR⁴;

L is selected from a bond, O, S, S—S, S(═O), S(═O)₂, S(═O)₂NR, NR, N—OR,C₁-C₁₂ alkylene, C₁-C₁₂ substituted alkylene, C₂-C₁₂ alkenylene, C₂-C₁₂substituted alkenylene, C₂-C₁₂ alkynylene, C₂-C₁₂ substitutedalkynylene, C(═O)NH, OC(═O)NH, NHC(═O)NH, C(═O), C(═O)NH(CH₂)_(n), or(CH₂CH₂O)_(n), where n is optionally 1, 2, 3, 4, 5, or 6; X is selectedfrom O, S, NH, NR, N—OR, N—NR₂, N—CR₂OR and N—CR₂NR₂; Ar is selectedfrom (a) a C₃-C₁₂ carbocycle, C₃-C₁₂ substituted carbocycle, C₆-C₂₀aryl, C₆-C₂₀ substituted aryl, C₂-C₂₀ heteroaryl, and C₂-C₂₀ substitutedheteroaryl; or (b) a saturated, unsaturated or aromatic ring or ringsystem having a mono- or bicyclic carbocycle or heterocycle containing 3to 12 ring atoms; R², R³ and R⁴ are each independently selected from H,F, Cl, Br, I, OH, —NH₂, —NH₃ ⁺, —NHR, —NR₂, —NR₃ ⁺, C₁-C₈ alkylhalide,carboxylate, sulfate, sulfamate, sulfonate, 5-7 membered ring sultam,C₁-C₈ alkylsulfonate, C₁-C₈ alkylamino, 4-dialkylaminopyridinium, C₁-C₈alkylhydroxyl, C₁-C₈ alkylthiol, —SO₂R, —SO₂Ar, —SOAr, —SAr, —SO₂NR₂,—SOR, —CO₂R, —C(═O)NR₂, 5-7 membered ring lactam, 5-7 membered ringlactone, —CN, —N₃, —NO₂, C₁-C₈ alkoxy, C₁-C₈ trifluoroalkyl, C₁-C₈alkyl, C₁-C₈ substituted alkyl, C₃-C₁₂ carbocycle, C₃-C₁₂ substitutedcarbocycle, C₆-C₂₀ aryl, C₆-C₂₀ substituted aryl, C₂-C₂₀ heteroaryl, andC₂-C₂₀ substituted heteroaryl, polyethyleneoxy, phosphonate, phosphate,and a prodrug moiety; when taken together on a single carbon, two R² ortwo R³ may form a spiro ring; R¹ is independently selected from CR₃,NRSO₂R, OC(═O)NR₂ OC(═O)R, SR, H, F, Cl, Br, I, OH, —NH₂, —NH₃ ⁺, —NHR,—NR₂, —NR₃ ⁺, C₁-C₈ alkylhalide, carboxylate, sulfate, sulfamate,sulfonate, 5-7 membered ring sultam, C₁-C₈ alkylsulfonate, C₁-C₈alkylamino, 4-dialkylaminopyridinium, C₁-C₈ alkylhydroxyl, C₁-C₈alkylthiol, —SO₂R, —SO₂Ar, —SOAr, —SAr, —SO₂NR₂, —SOR, —CO₂R, —C(═O)NR₂,5-7 membered ring lactam, 5-7 membered ring lactone, —CN, —N₃, —NO₂,C₁-C₈ alkoxy, C₁-C₈ trifluoroalkyl, C₁-C₈ alkyl, C₁-C₈ substitutedalkyl, C₃-C₁₂ carbocycle, C₃-C₁₂ substituted carbocycle, C₆-C₂₀ aryl,C₆-C₂₀ substituted aryl, C₂-C₂₀ heteroaryl, and C₂-C₂₀ substitutedheteroaryl, polyethyleneoxy, phosphonate, phosphate, and a prodrugmoiety; R is independently selected from H, C₁-C₈ alkyl, C₁-C₈substituted alkyl, C₆-C₂₀ aryl, C₆-C₂₀ substituted aryl, C₂-C₂₀heteroaryl, and C₂-C₂₀ substituted heteroaryl, polyethyleneoxy,phosphonate, phosphate, and a prodrug moiety; R^(X2) is independentlyselected from H, C₁-C₈ alkyl, C₁-C₈ substituted alkyl, C₆-C₂₀ aryl,C₆-C₂₀ substituted aryl, C₂-C₂₀ heteroaryl, and C₂-C₂₀ substitutedheteroaryl, polyethyleneoxy, phosphonate, phosphate, a prodrug moiety,and a protecting group; and the tautomers, salts, solvates, resolvedenantiomers and purified diastereomers thereof; with the proviso thatwhen Y=Z is C═C(OH), X is O, A¹ is C(═O), A² is C(R²)═C(R³), and Q isCH, then L is not a bond; and having a desired pharmaceutical activity;and (b) modifying said first structure by replacing one or more atoms ofsaid first structure with an organic substituent comprising aphosphonate group or incipient phosphonate group to provide a compoundhaving a second structure.
 11. A method of accumulating an HIV integraseinhibitor compound inside a white blood cell, comprising: (a) selectinga composition comprising a compound having a structure:

wherein: A¹ is independently selected from C(R²)₂, CR²OR, CR²OC(═O)R,C(═O), C(═S), CR²SR, and C(═NR), A² is independently selected fromC(R²)₂—C(R³)₂, C(R²)═C(R³) and C(═O)C(R³)₂; Q is CR⁴;

L is selected from a bond, O, S, S—S, S(═O), S(═O)₂, S(═O)₂NR, NR, N—OR,C₁-C₁₂ alkylene, C₁-C₁₂ substituted alkylene, C₂-C₁₂ alkenylene, C₂-C₁₂substituted alkenylene, C₂-C₁₂ alkynylene, C₂-C₁₂ substitutedalkynylene, C(═O)NH, OC(═O)NH, NHC(═O)NH, C(═O), C(═O)NH(CH₂)_(n), or(CH₂CH₂O), where n is optionally 1, 2, 3, 4, 5, or 6; X is selected fromO, S, NH, NR, N—OR, N—NR₂, N—CR₂OR and N—CR₂NR₂; Ar is selected from (a)a C₃-C₁₂ carbocycle, C₃-C₁₂ substituted carbocycle, C₆-C₂₀ aryl, C₆-C₂₀substituted aryl, C₂-C₂₀ heteroaryl, and C₂-C₂₀ substituted heteroaryl;or (b) a saturated, unsaturated or aromatic ring or ring system having amono- or bicyclic carbocycle or heterocycle containing 3 to 12 ringatoms; R², R³ and R⁴ are each independently selected from H, F, Cl, Br,I, OH, —NH₂, —NH₃ ⁺, —NHR, —NR₂, —NR₃ ⁺, C₁-C₈ alkylhalide, carboxylate,sulfate, sulfamate, sulfonate, 5-7 membered ring sultam, C₁-C₈alkylsulfonate, C₁-C₈ alkylamino, 4-dialkylaminopyridinium, C₁-C₈alkylhydroxyl, C₁-C₈ alkylthiol, —SO₂R, —SO₂Ar, —SOAr, —SAr, —SO₂NR₂,—SOR, —CO₂R, —C(═O)NR₂, 5-7 membered ring lactam, 5-7 membered ringlactone, —CN, —N₃, —NO₂, C₁-C₈ alkoxy, C₁-C₈ trifluoroalkyl, C₁-C₈alkyl, C₁-C₈ substituted alkyl, C₃-C₁₂ carbocycle, C₃-C₁₂ substitutedcarbocycle, C₆-C₂₀ aryl, C₆-C₂₀ substituted aryl, C₂-C₂₀ heteroaryl, andC₂-C₂₀ substituted heteroaryl, polyethyleneoxy, phosphonate, phosphate,and a prodrug moiety; when taken together on a single carbon, two R² ortwo R³ may form a spiro ring; R¹ is independently selected from CR₃,NRSO₂R, OC(═O)NR₂ OC(═O)R, SR, H, F, Cl, Br, I, OH, —NH₂, —NH₃ ⁺, —NHR,—NR₂, —NR₃ ⁺, C₁-C₈ alkylhalide, carboxylate, sulfate, sulfamate,sulfonate, 5-7 membered ring sultam, C₁-C₈ alkylsulfonate, C₁-C₈alkylamino, 4-dialkylaminopyridinium, C₁-C₈ alkylhydroxyl, C₁-C₈alkylthiol, —SO₂R, —SO₂Ar, —SOAr, —SAr, —SO₂NR₂, —SOR, —CO₂R, —C(═O)NR₂,5-7 membered ring lactam, 5-7 membered ring lactone, —CN, —N₃, —NO₂,C₁-C₈ alkoxy, C₁-C₈ trifluoroalkyl, C₁-C₈ alkyl, C₁-C₈ substitutedalkyl, C₃-C₁₂ carbocycle, C₃-C₁₂ substituted carbocycle, C₆-C₂₀ aryl,C₆-C₂₀ substituted aryl, C₂-C₂₀ heteroaryl, and C₂-C₂₀ substitutedheteroaryl, polyethyleneoxy, phosphonate, phosphate, and a prodrugmoiety; R is independently selected from H, C₁-C₈ alkyl, C₁-C₈substituted alkyl, C₆-C₂₀ aryl, C₆-C₂₀ substituted aryl, C₂-C₂₀heteroaryl, and C₂-C₂₀ substituted heteroaryl, polyethyleneoxy,phosphonate, phosphate, and a prodrug moiety; R^(X2) is independentlyselected from H, C₁-C₈ alkyl, C₁-C₈ substituted alkyl, C₆-C₂₀ aryl,C₆-C₂₀ substituted aryl, C₂-C₂₀ heteroaryl, and C₂-C₂₀ substitutedheteroaryl, polyethyleneoxy, phosphonate, phosphate, a prodrug moiety,and a protecting group; and the tautomers, salts, solvates, resolvedenantiomers and purified diastereomers thereof; with the proviso thatwhen Y=Z is C═C(OH), X is O, A¹ is C(═O), A² is C(R²)═C(R³), and Q isCH, then L is not a bond; and (b) administering said composition to asample.
 12. A method of claim 11 wherein said sample is a patient.
 13. Acompound having the structure:

wherein: A¹ is independently selected from C(R²)₂—C(R³)₂, C(R²)═C(R³),C(═O)C(R³)₂, C(R²)₂—C(R³)₂—C(R³)₂, C(R²)═C(R³)—C(R³)₂, and C(R²)₂—C(R³);A² is independently selected from C(R²)₂—C(R³)₂, C(R²)═C(R³), andC(═O)C(R³)₂; Q is CR⁴;

L is selected from a bond, O, S, S—S, S(═O), S(═O)₂, S(═O)₂NR, NR, N—OR,C₁-C₁₂ alkylene, C₁-C₁₂ substituted alkylene, C₂-C₁₂ alkenylene, C₂-C₁₂substituted alkenylene, C₂-C₁₂ alkynylene, C₂-C₁₂ substitutedalkynylene, C(═O)NH, OC(═O)NH, NHC(═O)NH, C(═O), C(═O)NH(CH₂)_(n), or(CH₂CH₂O)_(n), where n may be 1, 2, 3, 4, 5, or 6; X is selected from O,S, NH, NR, N—OR, N—NR₂, N—CR₂OR and N—CR₂NR₂; Ar is selected from (a) aC₃-C₁₂ carbocycle, C₃-C₁₂ substituted carbocycle, C₆-C₂₀ aryl, C₆-C₂₀substituted aryl, C₂-C₂₀ heteroaryl, and C₂-C₂₀ substituted heteroaryl;or (b) a saturated, unsaturated or aromatic ring or ring system having amono- or bicyclic carbocycle or heterocycle containing 3 to 12 ringatoms; R², R³ and R⁴ are each independently selected from H, F, Cl, Br,I, OH, —NH₂, —NH₃ ⁺, —NHR, —NR₂, —NR₃ ⁺, C₁-C₈ alkylhalide, carboxylate,sulfate, sulfamate, sulfonate, 5-7 membered ring sultam, C₁-C₈alkylsulfonate, C₁-C₈ alkylamino, 4-dialkylaminopyridinium, C₁-C₈alkylhydroxyl, C₁-C₈ alkylthiol, —SO₂R, —SO₂Ar, —SOAr, —SAr, —SO₂NR₂,—SOR, —CO₂R, —C(═O)NR₂, 5-7 membered ring lactam, 5-7 membered ringlactone, —CN, —N₃, —NO₂, C₁-C₈ alkoxy, C₁-C₈ trifluoroalkyl, C₁-C₈alkyl, C₁-C₈ substituted alkyl, C₃-C₁₂ carbocycle, C₃-C₁₂ substitutedcarbocycle, C₆-C₂₀ aryl, C₆-C₂₀ substituted aryl, C₂-C₂₀ heteroaryl, andC₂-C₂₀ substituted heteroaryl, polyethyleneoxy, phosphonate, phosphate,and a prodrug moiety; when taken together on a single carbon, two R² ortwo R³ may form a spiro ring; R¹ is independently selected from CR₃,NRSO₂R, OC(═O)NR₂ OC(═O)R, SR, H, F, Cl, Br, I, OH, —NH₂, —NH₃ ⁺, —NHR,—NR₂, —NR₃ ⁺, C₁-C₈ alkylhalide, carboxylate, sulfate, sulfamate,sulfonate, 5-7 membered ring sultam, C₁-C₈ alkylsulfonate, C₁-C₈alkylamino, 4-dialkylaminopyridinium, C₁-C₈ alkylhydroxyl, C₁-C₈alkylthiol, —SO₂R, —SO₂Ar, —SOAr, —SAr, —SO₂NR₂, —SOR, —CO₂R, —C(═O)NR₂,5-7 membered ring lactam, 5-7 membered ring lactone, —CN, —N₃, —NO₂,C₁-C₈ alkoxy, C₁-C₈ trifluoroalkyl, C₁-C₈ alkyl, C₁-C₈ substitutedalkyl, C₃-C₁₂ carbocycle, C₃-C₁₂ substituted carbocycle, C₆-C₂₀ aryl,C₆-C₂₀ substituted aryl, C₂-C₂₀ heteroaryl, and C₂-C₂₀ substitutedheteroaryl, polyethyleneoxy, phosphonate, phosphate, and a prodrugmoiety; R is independently selected from H, C₁-C₈ alkyl, C₁-C₈substituted alkyl, C₆-C₂₀ aryl, C₆-C₂₀ substituted aryl, C₂-C₂₀heteroaryl, and C₂-C₂₀ substituted heteroaryl, polyethyleneoxy,phosphonate, phosphate, and a prodrug moiety; R^(X2) is independentlyselected from H, C₁-C₈ alkyl, C₁-C₈ substituted alkyl, C₆-C₂₀ aryl,C₆-C₂₀ substituted aryl, C₂-C₂₀ heteroaryl, and C₂-C₂₀ substitutedheteroaryl, polyethyleneoxy, phosphonate, phosphate, a prodrug moiety,and a protecting group selected from the group consisting of benzyhydryl(CHPh₂), trialkylsilyl (R₃Si), 2-trimethylsiloxyethyl, alkoxymethyl(CH₂OR), and ester (C(═O)R); and the tautomers, salts, solvates,resolved enantiomers and purified diastereomers thereof.
 14. A compoundof claim 13 selected from the structures:


15. A compound of claim 13 selected from the structures:


16. A compound of claim 13 wherein R¹ is selected from R, OR, NR₂, NHR,NHSO₂R and NRSO₂R.
 17. A compound of claim 13 selected from thestructures:


18. A compound of claim 13 wherein R^(X2) is a protecting group selectedfrom the group consisting of benzyhydryl (CHPh₂), trialkylsilyl (R₃Si),2-trimethylsiloxyethyl, alkoxymethyl (CH₂OR), and ester (C(═O)R).
 19. Acompound of claim 13 having the structure:


20. A compound of claim 13 having Formula I:

wherein R^(X2) is H and X is O.
 21. A compound of claim 13 wherein L isnot a bond.
 22. A compound of claim 13 wherein R⁴ is H.
 23. A compoundof claim 13 wherein Ar is C₆-C₂₀ substituted aryl.
 24. A compound ofclaim 13 having at least one phosphonate group.
 25. A compound of claim13 wherein substituted alkyl, substituted alkylene, substitutedalkyenylene, substituted alkynylene, substituted carbocycle, substitutedaryl, and substituted heteroaryl are independently substituted with oneor more substituents selected from F, Cl, Br, I, OH, —NH₂, —NH₃ ⁺, —NHR,—NR₂, —NR₃ ⁺, C₁-C₈ alkylhalide, carboxylate, sulfate, sulfamate,sulfonate, 5-7 membered ring sultam, C₁-C₈ alkylsulfonate, C₁-C₈alkylamino, 4-dialkylaminopyridinium, C₁-C₈ alkylhydroxyl, C₁-C₈alkylthiol, —SO₂R, —SO₂Ar, —SOAr, —SAr, —SO₂NR₂, —SOR, —CO₂R, —C(═O)NR₂,5-7 membered ring lactam, 5-7 membered ring lactone, —CN, —N₃, —NO₂,C₁-C₈ alkoxy, C₁-C₈ trifluoroalkyl, C₁-C₈ alkyl, C₃-C₁₂ carbocycle,C₆-C₂₀ aryl, C₂-C₂₀ heteroaryl, polyethyleneoxy, phosphonate, phosphate,and a prodrug moiety.
 26. The compound of claim 13 wherein A¹ isCH₂—CH₂, C(CH₃)₂—CH₂, CH═CH or CH₂—CH₂—CH₂.
 27. The compound of claim 20wherein L is CH₂; and Ar is substituted phenyl.
 28. The compound ofclaim 27 wherein Ar is 4-fluorophenyl.
 29. The compound of claim 20wherein R², R³ and R⁴ are each H.
 30. The compound of claim 20 whereinA¹ is CH═CH; and R², R³ and R⁴ are each H.
 31. The compound of claim 13wherein Ar-L is selected from the structures:


32. A compound of claim 20 having the formula


33. A compound of claim 20 having the structure:


34. A compound of claim 20 wherein Ar-L is para-fluorobenzyl.
 35. Acompound of claim 13 wherein R¹ is selected from CR₃, C(═O)NR₂,OC(═O)OR, OC(═O)NR₂, OC(═O)R, OSO₂NR₂ (sulfamate), NR₂, NRSO₂R, SR,S(O)R, SO₂R and SO₂NR₂ (sulfonamide).
 36. The compound of claim 35wherein at least one R is a prodrug moiety.
 37. A compound of claim 13wherein at least one of R¹, R², R³, and R⁴ is selected from thestructures:


38. A compound of claim 13 wherein at least one of R¹, R², R³, and R⁴ isselected from the structures:


39. A compound of claim 13 wherein at least one of R¹, R², R³, and R⁴ isselected from the structures:


40. A compound of claim 13 wherein at least one of R¹, R², R³, and R⁴ isa lactam having the structures:

a sultam having the structures:


41. A compound of claim 13 wherein Ar is selected from the structures:

where the wavy line

indicates the covalent attachment site to L.
 42. A compound of claim 13wherein Ar is selected from the structures:

where n is 1 to
 6. 43. A compound of claim 13 wherein Ar is selectedfrom the structures:


44. A compound of claim 13 comprising a prodrug moiety selected from thestructures:

wherein R⁵ is —CR₂CO₂R⁷ where R⁶ and R⁷ are independently H or C₁-C₈alkyl.
 45. The compound of claim 13 comprising a phosphonate or prodrugmoiety having the structure:

wherein: Y¹ is independently O, S, N(R^(x)), N(O)(R^(x)), N(OR^(x)),N(O)(OR^(x)), or N(N(R^(x))₂; Y² is independently a bond, O, N(R^(x)),N(O)(R^(x)), N(OR^(x)), N(O)(OR^(x)), N(N(R^(x))₂), —S(O)— (sulfoxide),—S(O)₂— (sulfone), —S— (sulfide), or —S—S— (disulfide); M2 is 0, 1 or 2;M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; M12b is 0, 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11, or 12; R^(y) is independently H, C₁-C₆ alkyl,C₁-C₆ substituted alkyl, C₆-C₂₀ aryl, C₆-C₂₀ substituted aryl, or aprotecting group, or where taken together at a carbon atom, two vicinalR^(y) groups form a carbocycle or a heterocycle; and R_(x) isindependently H, C₁-C₆ alkyl, C₁-C₆ substituted alkyl, C₆-C₂₀ aryl,C₆-C₂₀ substituted aryl, or a protecting group, or the formula:

where M1a, M1c, and M1d are independently 0 or 1, and M12c is 0, 1, 2,3, 4, 5, 6, 7, 8, 9, 10, 11 or
 12. 46. The compound of claim 45 whereinthe phosphonate or prodrug moiety has the structure:


47. The compound of claim 46 wherein the phosphonate or prodrug moietyhas the structure:

where Y^(2b) is O or N(R^(x)).
 48. The compound of claim 46 wherein thephosphonate or prodrug moiety has the structure:

where W⁵ is a carbocycle, and Y^(2c) is O, N(R^(y)) or S.
 49. Thecompound of claim 48 wherein W⁵ is selected from the structures:


50. The compound of claim 46 wherein the phosphonate or prodrug moietyhas the structure:


51. The compound of claim 13 wherein the phosphonate or prodrug moietyhas the structure:

wherein Y^(2b) is O or N(R^(x)); M12d is 1, 2, 3, 4, 5, 6, 7 or 8; R¹ isH or C₁-C₆ alkyl; and the phenyl carbocycle is substituted with 0 to 3R² groups where R² is C₁-C₆ alkyl or substituted alkyl.
 52. The compoundof claim 13 wherein the phosphonate or prodrug moiety has the structure:


53. The compound of claim 45 wherein Rx is selected from the structures:


54. A compound of claim 13 wherein none of R², R³, R⁴, R, or R^(X2) is aprodrug moiety.
 55. A compound that is


56. A compound of claim 13 substituted with a phosphonate or phosphonateprodrug moiety and capable of accumulating in human PBMC.
 57. Thecompound of claim 56 wherein the intracellular half-life of the compoundor an intracellular metabolite of the compound in human PBMC isincreased by at least about 50% when compared to the analog of thecompound not having the a phosphonate or phosphonate prodrug moiety. 58.The compound of claim 57 wherein the half-life is improved by at leastabout 100%.
 59. The compound of claim 56 wherein the intracellularhalf-life of a metabolite of the compound in human PBMC is increased byat least about 50% when compared to the analog of the compound nothaving the a phosphonate or phosphonate prodrug moiety.
 60. The compoundof claim 59 wherein the half-life is improved by at least about 100%.61. The compound of claim 60 wherein the half-life is improved bygreater than 100%.
 62. A pharmaceutical composition comprising atherapeutically effective amount of a compound of claim 13 and apharmaceutically acceptable carrier.
 63. The pharmaceutical compositionof claim 62 further comprising a therapeutically effective amount of anAIDS treatment agent selected from an HIV inhibitor agent, ananti-infective agent, and an immunomodulator.
 64. The pharmaceuticalcomposition of claim 63 wherein the HIV inhibitor agent is anHIV-protease inhibitor.
 65. The pharmaceutical composition of claim 63wherein the HIV inhibitor agent is a nucleoside reverse transcriptaseinhibitor.
 66. The pharmaceutical composition of claim 65 wherein saidnucleoside reverse transcriptase inhibitor is 3′-azido-3′-deoxythymidine(zidovudine, AZT), 2′-deoxy-3′-thiacytidine (3TC),2′,3′-dideoxy-2′,3′-didehydroadenosine (D4A),2′,3′-dideoxy-2′,3′-didehydrothymidine (D4T), carbovir (carbocyclic2′,3′-dideoxy-2′,3′-didehydroguanosine), 2′,3′-dideoxycytidine (ddC),2′,3′-dideoxyadenosine (ddA), 2′,3′-dideoxyinosine (ddI), PMEA, or PMPA.67. The composition of claim 63 wherein the HIV inhibitor agent is anon-nucleoside reverse transcriptase inhibitor.
 68. A process for makinga pharmaceutical composition comprising combining a compound of claim 13and a pharmaceutically acceptable carrier.
 69. A method of inhibitingHIV integrase, comprising the administration to a mammal in need of suchtreatment of a therapeutically effective amount of a compound of claim13.
 70. A method of treating infection by HIV, or of treating AIDS orARC, comprising administration to a mammal in need of such treatment ofa therapeutically effective amount of a compound of claim
 13. 71. Methodof treating a disorder affecting white blood cells, comprising:administering a compound of claim 13 comprising a phosphonate prodrug toa patient in need of white-blood-cell targeting.
 72. A method oftargeting a compound to white blood cells, comprising: (a) selecting acompound of claim 13 having a desired pharmaceutical activity and havinga first structure; and (b) modifying said first structure by replacingone or more atoms of said first structure with an organic substituentcomprising a phosphonate group or incipient phosphonate group to providea compound having a second structure.
 73. A method of accumulating anHIV integrase inhibitor compound inside a white blood cell, comprising:(a) selecting a composition comprising a compound of claim 13; and (b)administering said composition to a sample.
 74. A method of claim 73wherein said sample is a patient.